Morphan and Morphinan Analogues, and Methods of Use

ABSTRACT

The present application relates to analogues of morphan and morphinan, compositions thereof, and methods for treating a disease or condition comprising administering an effective amount of the compounds or compositions to a subject in need thereof.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/827,210, filed May 24, 2013, the content of which is incorporatedherein by reference in its entirety.

BACKGROUND

Depression (also known as depressive disorders or depressive symptoms)includes common but serious disorders of the brain characterized bycombinations of signs and symptoms that may include feelings ofhopelessness, guilt, worthlessness, and/or sadness alongside changes insleep and/or eating patterns. While complex depressive disorders arethought to be caused by multiple factors, it is widely accepted thatthese disorders generally have a neurochemical component. Currenttreatment regimens often consist of a combination of psychotherapy andone or more medications to regulate neurotransmitters such as dopamine,serotonin and norepinephrine.

Current pharmacological methods of treatment for depressive disorderscan be efficacious, but they often have significant drawbacks. Manyanti-depressants have a latency period of two to three weeks, a delaythat can be life-threatening to a patient who is depressed. After thisinitial period, if a chosen therapeutic shows little or no effect on thesymptoms of the patient, the treating physician may alter thetherapeutic regimen by increasing the dosage of the chosen drug or byrecommending an entirely new compound. Even after a medication provesefficacious, the patient may suffer side effects such as dizziness,weight gain, and a loss of libido. The patient may also develop atolerance to the drug, leading them to take ever-increasing doses inorder to achieve similar results. In certain cases, chemical dependencemay also develop, leading to potential abuse and, in the case of abruptdiscontinuation, major withdrawal (including the risk of grand malseizures and death).

While certain treatments for depressive disorders do exist, manycommonly used therapeutics suffer from significant drawbacks includinginefficacy, latency periods, tolerance, and chemical dependence. Thereis therefore an urgent need for new and improved methods of treatmentfor these disorders that may be used alone or in conjunction withexisting therapeutic modalities.

SUMMARY OF THE INVENTION

Provided herein are morphan and morphinan analogues, pharmaceuticalcompositions thereof, and methods of using such compounds to treat oralleviate a disease or condition. Such diseases include, for example, adepressive symptom, pain, pruritis, diarrhea, irritable bowel syndrome,gastrointestinal motility disorder, obesity, respiratory depression,convulsions, coughing, hyperalgesia, and drug addiction.

In one aspect, provided herein is compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is cyclobutyl or

-   -   R₂ is H or methoxy; and    -   R₃ and R₄ are each, independently, H, hydroxyl, or NR₅R₆ wherein        R₅ and R₆ are each independently H, alkyl, or substituted acyl,        or alternatively, R₃ and R₄, together with the carbon atom to        which they are attached, form C═O or C═CH₂.

In one embodiment of Formula I, R₁ is cyclobutyl. In another embodiment,R₂ is H. In still another embodiment, R₃ or R₄, but not both, ishydroxyl, or alternatively, R₃ and R₄, together with the carbon atom towhich they are attached, form C═O.

In another aspect, provided herein is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is C₁-C₆ alkyl, C₂-C₆ alkenyl, cycloalkyl, heterocyclyl,hydroxyalkyl, or alkoxyalkyl;

R₂ and R₃ are each C₁-C₄ alkyl, or alternatively, R₂ and R₃, togetherwith the carbon atoms to which they are attached, form a 6-memberedcarbocyclic ring which is optionally substituted with a ketone, ahydroxyl, or a NR₅R₆ group wherein R₅ and R₆ are each independently H,alkyl, or substituted acyl group;

when

is a single bond, R₄ is H; and

when

is a double bond, R₄ is O.

In one embodiment of Formula II, R₁ is C₂-C₆ alkenyl or cycloalkyl. Inanother embodiment, R₂ and R₃ are each methyl. In still anotherembodiment,

is a single bond, and R₄ is H.

In still another aspect, provided herein is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is C₁-C₆ alkyl, C₂-C₆ alkenyl, cycloalkyl, heterocyclyl,hydroxyalkyl, or alkoxyalkyl;

R₂ and R₃ are each H or C₁-C₄ alkyl, or alternatively, R₂ and R₃,together with the carbon atoms to which they are attached, form a6-membered unsubstituted carbocyclic ring, or a 6-membered carbocyclicring optionally substituted with a hydroxyl, a ketone, or a NR₅₀R₆₀group, wherein R₅₀ and R₆₀ are each independently H, alkyl, orsubstituted acyl;

R₄ and R₅ are each, independently, H, hydroxyl, or taken together withthe carbon atom to which they are attach to, form a C═O group;

R₆ is unsubstituted or substituted C₆-C₁₀ aryl, or substituted orunsubstituted heteroaryl comprising one or two 5- or 6-membered ringsand 1-4 heteroatoms selected from N, O and S; and

R₇ and R₈ are each, independently, H or hydroxyl.

In one embodiment of Formula III, R₁ is C₂-C₆ alkenyl or cycloalkyl. Inanother embodiment, R₂ and R₃, together with the carbon atoms to whichthey are attached, form a 6-membered unsubstituted carbocyclic ring or a6-membered carbocyclic ring substituted with a hydroxyl or a ketone. Instill another embodiment, R₄ and R₅, taken together with the carbon atomto which they are attach to, form a C═O group. In yet anotherembodiment, R₆ is substituted heteroaryl comprising one or two 5- or6-membered rings and 1-4 heteroatoms selected from N, O and S.

In still another aspect, provided herein is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is cyclopropyl or cyclobutyl;

X is H, hydroxyl, or methoxy;

Y and Z are each, independently, H, hydroxyl, or NR₅R₆ wherein R₅ and R₆are each independently H, alkyl or substituted acyl, or alternatively, Yand Z, together with the carbon atom to which they are attached, formC═O or C═CH₂;

R₃ is H or hydroxyl; and

R₂ is —C(O)NH₂, or —NH—CH₂-phenyl, wherein the phenyl can besubstituted.

In one embodiment of Formula IV, R₁ is cyclopropyl. In anotherembodiment, X is H or hydroxyl. In still another embodiment, Y and Z areeach, independently, H or hydroxyl, or alternatively, Y and Z, togetherwith the carbon atom to which they are attached, form C═O. In yetanother embodiment, R₂ is —C(O)NH₂.

In another embodiment, provided herein is a compound selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.

In one particular aspect, provided herein is a compound selected from

or a pharmaceutically acceptable salt thereof.

In certain embodiments of the above-described aspects, the compound is aμ opioid receptor agonist having an Emax of 5% to 45% in a GTPγS bindingassay. In particular embodiments, the Emax is 15% to 35% in a GTPγSbinding assay. In other embodiments, the agonist has a low risk ofopioid dependence, opioid addiction, and/or symptoms of opioidwithdrawal.

In certain embodiments of the above-described aspects, the compoundexhibits a maximal dopamine efflux in the nucleus accumbens of 125% to300% over baseline in a rat. In particular embodiments, the compoundexhibits a maximal dopamine efflux in the nucleus accumbens of 200% to300% over baseline in a rat.

In other embodiments of the above-described aspects, the compound doesnot attenuate thermal pain in a rodent hot plate model when administeredat a dose of at least 1 mg/kg. In particular embodiments, the compounddoes not attenuate thermal pain in a rodent hot plate model whenadministered at a dose of at least 3 mg/kg. In other embodiments, thecompound does not attenuate thermal pain in a rodent hot plate modelwhen administered at a dose of 10 mg/kg.

In another aspect, provided herein is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and the compound of theabove-described aspects.

In still another aspect, provided herein is a method of treating adepressive symptom in a subject in need thereof, wherein the methodcomprises administering to the subject an effective amount of a μ opioidreceptor agonist that exhibits an Emax of 5% to 45% in a GTPγS bindingassay. In particular embodiments, the Emax is 15% to 35% in a GTPγSbinding assay. In other embodiment, said agonist has a low risk ofopioid dependence, opioid addiction, and/or symptoms of opioidwithdrawal.

In another aspect, provided herein is a method of treating a depressivesymptom in a subject in need thereof, wherein the method comprisesadministering to the subject an effective amount of a compound having amaximal dopamine efflux in the nucleus accumbens of 125% to 300% overbase line in a rat. In particular embodiments, the compound has amaximal dopamine efflux in the nucleus accumbens of 200% to 300% overbase line in a rat.

In still another aspect, provided herein is a method of treating adepressive symptom in a subject in need thereof, wherein the methodcomprises administering to the subject an effective amount of a compoundthat does not attenuate thermal pain in a rodent hot plate model whenadministered at a dose of at least 1 mg/kg. In particular embodiments,the compound does not attenuate thermal pain in a rodent hot plate modelwhen administered at a dose of at least 3 mg/kg. In other embodiments,the compound does not attenuate thermal pain in a rodent hot plate modelwhen administered at a dose of 10 mg/kg.

In yet another aspect, provided herein is a method of treating adepressive symptom in a subject in need thereof, wherein the methodcomprises administering to the subject any one of the compounds providedherein, or a pharmaceutically acceptable salt thereof.

In certain embodiments of the methods provided herein, the depressivesymptom is depressed mood, loss of pleasure, loss of appetite, sleepdisturbance, psychomotor changes, fatigue, and/or post-partumdepression.

In other embodiments, the depressive symptom is associated with a mentalcondition, wherein the mental condition is schizoaffective disorder,and/or seasonal affective disorder.

In still other embodiments, the depressive symptom is acute stressdisorder, adjustment disorders with depressed mood, Asperger syndrome,attention deficit, bereavement, bipolar I disorder, bipolar II disorder,borderline and personality disorder, cyclothymia and dysthymia,depression such as major depressive disorder (MDD) andtreatment-resistant disorder (TRD), Dysthymic disorder, hyperactivitydisorder, impulse control disorder, mixed mania, obsessive-compulsivepersonality disorder (OCD), paranoid, post-traumatic stress disorder,seasonal affective disorder, self-injury separation, sleep disorder,substance-induced mood disorder, Tourette syndrome and tic disorder,and/or Trichotillomania.

In yet other embodiments, the depressive symptom is an anxiety disorder,wherein the anxiety disorder is generalized anxiety disorder, panic,agoraphobia, acute stress, and/or post-traumatic stress disorder.

In certain embodiments, the depressive symptom is associated withchronic or recurrent depression.

Furthermore, provided herein is a method of treating a disease orcondition associated with the group consisting of pain, pruritis,diarrhea, irritable bowel syndrome, gastrointestinal motility disorder,obesity, respiratory depression, convulsions, coughing, hyperalgesia,and drug addiction in a subject, which comprises administering to thesubject a pharmaceutical composition comprising any one of the compoundsdisclosed herein or a pharmaceutically acceptable salt thereof. In oneembodiment, the drug addiction is selected from heroin, cocaine,nicotine, amphetamine and alcohol addiction.

Also provided herein is a method of treating a disease or condition in asubject by altering a response mediated by an opioid receptor, whereinthe method comprises bringing into contact with the opioid receptor aneffective amount of any one of the compounds provided herein.

In preferred embodiments of all of the methods disclosed herein, thesubject is a human.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the results of experiments measuring the antinociceptiveeffects of Compound A, either alone or in combination with morphine,using a rat hot plate assay.

FIG. 2 depicts the results of experiments measuring the antinociceptiveeffects of Compound A, or buprenorphine using a rat hot plate assay.

FIG. 3 depicts the results of in vivo microdialysis experimentsmeasuring dopamine release in the rat nucleus accumbens induced byCompound A and buprenorphine.

FIG. 4 depicts the results of experiments measuring the antinociceptiveeffects of morphine, Compound B, Compound C, Compound D and Compound E,using a rat hot plate assay.

FIG. 5 depicts the results of in vivo microdialysis experimentsmeasuring dopamine release in the rat nucleus accumbens induced bydifferent doses of Compound B.

FIG. 6 depicts the results of in vivo microdialysis experimentsmeasuring dopamine release in the rat nucleus accumbens induced bydifferent doses of Compound C.

FIG. 7 depicts the results of in vivo microdialysis experimentsmeasuring dopamine release in the rat nucleus accumbens induced bydifferent doses of Compound D.

FIG. 8 depicts the results of in vivo microdialysis experimentsmeasuring dopamine release in the rat nucleus accumbens induced bydifferent doses of Compound E.

FIG. 9 depicts the results of in vivo Forced Swim Test measuringreduction of immobility in rats induced by different doses of CompoundA, B or C.

DETAILED DESCRIPTION Compounds of the Invention

This disclosure is directed toward morphan and morphinan analogues, andpharmaceutical compositions thereof for use in treatment of a disease orcondition. Provided herein are compounds and compositions thereof usefulto treat a depressive symptom, such as depressed mood, loss of pleasure,loss of appetite, sleep disturbance, psychomotor changes, fatigue,and/or post-partum depression. Provided herein are also compounds andcompositions thereof useful in treating pain, pruritis, diarrhea,irritable bowel syndrome, gastrointestinal motility disorder, obesity,respiratory depression, convulsions, coughing, hyperalgesia, and/or drugaddiction. In one particular embodiment, provided herein are compoundsand compositions thereof useful to treat depression.

In one aspect, provided herein is a compound of the Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is cyclobutyl or

R₂ is H or methoxy; and

R₃ and R₄ are each, independently, H, hydroxyl, or NR₅R₆ wherein R₅ andR₆ are each independently H, alkyl, or substituted acyl, oralternatively, R₃ and R₄, together with the carbon atom to which theyare attached, form C═O or C═CH₂.

In one embodiment of Formula I, substituted acyl is defined as follows:

wherein R₁₁ is linear or branched C₁-C₆ alkyl; R₁₂ is halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy; and R₁₃ is aryl or heteroaryl.

In another embodiment of Formula I, R₁ is cyclobutyl.

In another embodiment of Formula I, R₂ is methoxy. In anotherembodiment, R₂ is H.

In still another embodiment, R₃ or R₄, but not both, is hydroxyl, oralternatively, R₃ and R₄, together with the carbon atom to which theyare attached, form C═O.

In another aspect, provided herein is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is cyclobutyl, cyclopentyl,

R₂ is H, hydroxyl, or methoxy; and

R₃ and R₄ are each, independently, H, hydroxyl, or NR₅R₆ wherein R₅ andR₆ are each independently H, alkyl, or substituted acyl, oralternatively, R₃ and R₄, together with the carbon atom to which theyare attached, form C═O or C═CH₂.

In one embodiment of Formula Ia, R₁ is cyclobutyl,

In one embodiment of Formula Ia, substituted acyl is defined as follows:

wherein R₁₁ is linear or branched C₁-C₆ alkyl; R₁₂ is halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy; and R₁₃ is aryl or heteroaryl.

In one embodiment of Formula Ia, R₁ is cyclobutyl.

In another embodiment of Formula Ia, R₂ is H.

In still another embodiment of Formula Ia, R₃ or R₄, but not both, ishydroxyl, or alternatively, R₃ and R₄, together with the carbon atom towhich they are attached, form C═O.

In one aspect, provided herein is a compound of the Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is cyclopropyl, cyclobutyl, cyclopentyl,

R₂ is H, hydroxyl, or methoxy; and

R₃ is H or hydroxyl, and

R₄ is hydroxyl, or NR₅R₆ wherein R₅ and R₆ are each independently H,alkyl, or substituted acyl;

or alternatively, R₃ and R₄, together with the carbon atom to which theyare attached, form C═O or C═CH₂.

In one embodiment of Formula Ib, R₁ is cyclobutyl or

In one embodiment of Formula Ib, R₁ is cyclobutyl.

In another embodiment of Formula Ib, R₂ is methoxy. In anotherembodiment, R₂ is H.

In another embodiment of Formula Ib, substituted acyl is defined asfollows:

wherein R₁₁ is linear or branched C₁-C₆ alkyl; R₁₂ is halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy; and R₁₃ is aryl or heteroaryl.

In still another embodiment, R₃ is H and R₄ is hydroxyl, oralternatively, R₃ and R₄, together with the carbon atom to which theyare attached, form C═O or C═CH₂.

In another aspect, provided herein is a compound of Formula Ic:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is cyclobutyl, cyclopentyl,

R₅ and R₆ are each independently H, alkyl, or substituted acyl, whereinthe substituted acyl is:

wherein R₁₁ is C₁-C₆ linear or branched alkyl; R₁₂ is H, halo, C₁-C₆alkyl, or C₁-C₆ alkoxy; and R₁₃ is H, aryl, or heteroaryl.

In one embodiment of Formula Ic, R₁ is cyclobutyl. In anotherembodiment, R₁ is cyclopentyl.

In another aspect, provided herein is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is C₁-C₆ alkyl, C₂-C₆ alkenyl, cycloalkyl, heterocyclyl,hydroxyalkyl, or alkoxyalkyl;

R₂ and R₃ are each C₁-C₄ alkyl , or alternatively, R₂ and R₃, togetherwith the carbon atoms to which they are attached, form a 6-memberedcarbocyclic ring, wherein the carbocyclic ring is optionally substitutedwith a ketone, a hydroxyl, or a NR₅R₆ group wherein R₅ and R₆ are eachindependently H, alkyl, or substituted acyl;

when

is a single bond, R₄ is H; and

when

is a double bond, R₄ is O.

In one embodiment of Formula (II), R₁ is C₂-C₆ alkenyl or cycloalkyl. Ina particular embodiment, R₁ can be cyclopropyl or cyclobutyl.

In another embodiment of Formula II, substituted acyl is defined asfollows:

wherein R₁₁ is linear or branched C₁-C₆ alkyl; R₁₂ is halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy; and R₁₃ is aryl or heteroaryl.

In another embodiment of Formula (II), R₂ and R₃ are each methyl.

In still another embodiment of Formula (II),

is a single bond, and R₄ is H.

In another aspect, provided herein is a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is C₁-C₆ alkyl, C₂-C₆ alkenyl, hydroxyalkyl, alkoxyalkyl, cyclobutyl,or cyclopentyl;

R_(1a) is H or methyl;

R₂ and R₃ are each C₁-C₁ alkyl , or alternatively, R₂ and R₃, togetherwith the carbon atoms to which they are attached, form a 6-memberedcarbocyclic ring, wherein the carbocyclic ring is substituted with aketone, or a hydroxyl, or a NR₅R₆ group, wherein R₅ and R₆ are eachindependently H, alkyl or substituted acyl;

when

is a single bond, R₄ is H; and

when

is a double bond, R₄ is O.

In one embodiment of Formula (IIa), R₁ is cyclobutyl, cyclopentyl,

In one embodiment of Formula (IIa), substituted acyl is defined asfollows:

wherein R₁₁ is linear or branched C₁-C₆ alkyl; R₁₂ is halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy; and R₁₃ is aryl or heteroaryl.

In one embodiment of Formula (IIa), R₁ is cyclobutyl. In anotherembodiment, R₁ is cyclopentyl. In still another embodiment, R₁ is

In one embodiment of Formula (IIa), R₂ and R₃ are each methyl. Inanother embodiment, R₂ and R₃, together with the carbon atoms to whichthey are attached, form a 6-membered carbocyclic ring, wherein thecarbocyclic ring is substituted with a ketone, or a hydroxyl, or a NR₅R₆group.

In another embodiment, R_(1a) is H.

In still another embodiment of Formula (IIa),

is a single bond, and R₄ is H.

In yet another embodiment of Formula (IIa),

is a double bond, and R₄ is O.

In still another aspect, provided herein is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is C₁-C₆ alkyl, C₂-C₆ alkenyl, cycloalkyl, heterocyclyl,hydroxyalkyl, or alkoxyalkyl;

R₂ and R₃ are each H or C₁-C₄ alkyl, or alternatively, R₂ and R₃,together with the carbon atoms to which they are attached, form a6-membered unsubstituted carbocyclic ring, or a 6-membered carbocyclicring optionally substituted with a hydroxyl, a ketone, or a NR₅₀R₆₀group, wherein R₅₀ and R₆₀ are each independently H, alkyl, orsubstituted acyl;

R₄ and R₅ are each, independently, H, hydroxyl, or taken together withthe carbon atom to which they are attach to form a C═O group;

R₆ is unsubstituted or substituted C₆-C₁₀ aryl, or substituted orunsubstituted heteroaryl comprising one or two 5- or 6-membered ringsand 1-4 heteroatoms selected from N, O and S; and

R₇ and R₈ are each, independently, H or hydroxyl.

In one embodiment of Formula (III), R₁ is C₂-C₆ alkenyl or cycloalkyl.In a particular embodiment, R₁ can be cyclopropyl or cyclobutyl.

In another embodiment of Formula (III), R₂ and R₃ are each H, methyl orethyl.

In another embodiment of Formula (III), R₂ and R₃, together with thecarbon atoms to which they are attached, form a 6-membered unsubstitutedcarbocyclic ring or a 6-membered carbocyclic ring substituted with ahydroxyl or a ketone.

In another embodiment of Formula (III), substituted acyl is defined asfollows:

wherein R₁₁ is linear or branched C₁-C₆ alkyl; R₁₂ is halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy; and R₁₃ is aryl or heteroaryl.

In another embodiment of Formula (III), R₄ and R₅, taken together withthe carbon atom to which they are attached, form a C═O group.

In another embodiment of Formula (III), R₄ and R₅ are each,independently, H or hydroxyl.

In still another embodiment of Formula (III), R₆ is substitutedheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O and S.

In yet another embodiment of Formula (III), R₆ is unsubstituted orsubstituted C6-C10 aryl.

In another aspect, provided herein is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is cyclopropyl or cyclobutyl;

X is H, hydroxyl, or methoxy;

Y and Z are each, independently, H, hydroxyl, or NR₅R₆ wherein R₅ and R₆are each independently H, alkyl or substituted acyl, or alternatively, Yand Z, together with the carbon atom to which they are attached, formC═O or C═CH₂;

R₃ is H or hydroxyl; and

R₂ is —C(O)NH₂, or —NH—CH₂-phenyl, wherein the phenyl can besubstituted.

In one embodiment of Formula IV, substituted acyl is defined as follows:

wherein R₁₁ is linear or branched C₁-C₆ alkyl; R₁₂ is halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy; and R₁₃ is aryl or heteroaryl.

In one embodiment of Formula (IV), R₁ is cyclopropyl.

In another embodiment of Formula (IV), X is H or hydroxyl.

In still another embodiment of Formula (IV), Y and Z are each,independently, H or hydroxyl, or alternatively, Y and Z, together withthe carbon atom to which they are attached, form C═O or C═CH₂.

In another embodiment of Formula (IV), R₂ is —NH—CH₂-phenyl, wherein thephenyl can be substituted. In a particular embodiment, the phenyl of—NH—CH₂-phenyl can have one to three substituents independently selectedfrom the group consisting of hydroxyl, alkyl, and alkoxy.

In yet another embodiment of Formula (IV), R₂ is —C(O)NH₂.

In another aspect, provided herein is a compound of Formula IVa:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃ or C₅-C₁₀ cycloalkyl, heterocyclyl,hydroxyalkyl, or alkoxyalkyl;

R_(1a) is H or methyl;

X is H, hydroxyl, or methoxy;

Y and Z are each, independently, H, hydroxyl, or NR₅R₆ wherein R₅ and R₆are each independently H, alkyl or substituted acyl, or alternatively, Yand Z, together with the carbon atom to which they are attached, formC═O or C═CH₂;

R₃ is H or hydroxyl; and

R₂ is —NH—CH₂-phenyl, wherein the phenyl can be further substituted.

In one embodiment of Formula (IVa), R₁ is cyclopropyl.

In one embodiment of Formula (Iva), substituted acyl is defined asfollows:

wherein R₁₁ is linear or branched C₁-C₆ alkyl; R₁₂ is halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy; and R₁₃ is aryl or heteroaryl.

In another embodiment of Formula (IVa), X is H or hydroxyl.

In still another embodiment of Formula (IVa), Y and Z are both H, oralternatively, Y and Z, together with the carbon atom to which they areattached, form C═O or C═CH₂.

In another embodiment of Formula (Iva), Y is H, and Z is hydroxyl orNR₅R₆.

In another embodiment of Formula (IVa), the phenyl of —NH—CH₂-phenyl canhave one to three substituents independently selected from the groupconsisting of hydroxyl, alkyl, and alkoxy.

In yet another embodiment of Formula (IVa), R_(1a) is H.

In still another aspect, provided herein is a compound selected from

In yet another aspect, provided herein is a compound of Formula V

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is cyclobutyl, cyclopropyl,

R₂ is H, OH, or methoxy; and

R₃ and R₄ are are each, independently, H, hydroxyl or NR₅R₆ wherein R₅and R₆ are each independently H, alkyl or substituted acyl, oralternatively, R₃ and R₄, together with the carbon atom to which theyare attached, form C═O or C═CH₂.

In one embodiment of Formula V, substituted acyl is defined as follows:

wherein R₁₁ is linear or branched C₁-C₆ alkyl; R₁₂ is halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy; and R₁₃ is aryl or heteroaryl.

In one embodiment of Formula V, R₃ and R₄, together with the carbon atomto which they are attached, form C═O or C═CH₂.

In another embodiment of Formula V, R₃ is H, and R₄ is hydroxyl orNR₅R₆.

In one embodiment of Formula V, R₃ is H, and R₄ is hydroxyl.

In another embodiment, provided herein are the compounds shown in TableA, or pharmaceutically acceptable salts thereof.

TABLE A

Compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19

Compound 20

Compound 21

In another embodiment, provided herein are the compounds shown in TableB, or pharmaceutically acceptable salts thereof.

TABLE B Structure mu_Ki mu_EC50 mu_Emax mu_IC50 mu_Imax

0.28   1.4 ± 0.06  30 ± 2.2 4.2 ± 0.6  71 ± 0.8

0.11  1.1 ± 0.3 29 ± 1  2.0 ± 0.3 74 ± 2 

0.097  0.53 28 1.3 65

0.22  3.3 33 14   69

0.097  0.39 42 1.1 54

0.12  2.1 38 5   63

0.13  1.5 44 3.7 66

0.56  4.2 49 34   54

0.5  15   35 51   70

0.19   2.3  36 14   55

2.1  110 (12) 43 (7) >1300 (280) 53% @ 10 uM

0.16    1 ± 0.11 31 ± 1  2.2 ± 0.5  69 ± 1.5

0.59 ± 0.07 2.8 ± 0.3 18 ± 1  47   78.5 ± 4.5 

0.10 ± 0.04 0.98 ± 0.12 18 ± 5  3.8 80 ± 1 

In another embodiment, provided herein are the compounds shown in TableC, or pharmaceutically acceptable salts thereof.

TABLE C Structure mu_Ki mu_EC50 mu_Emax mu_IC50 mu_Imax

0.1 3.5 32 3.3 73

22 60 27 950 65

0.82 13 26 85 76

4.6 84 23 210 74

0.11 4.8 53 26 37

1.2 16 44 85

0.68 22 25 47 83

0.27 5.2 32 18 59

0.37 2.9 46 1.5 43

2.3 62 18 170 87

3 41 19 170 83

23 190 35 >3000 57 @ 10 uM

4.4 20 20 340 76

1.2 1.6 44 85

In yet another embodiment, provided herein are the compounds shown inTable E, or pharmaceutically acceptable salts thereof.

TABLE E

The compounds of the present invention are useful for treating a diseaseor condition by altering a response of an opioid receptor. It has beendiscovered that compounds having an Emax of 5% to 45% (e.g., 15% to 35%)in a GTPγS binding assay are particularly suitable for treating adepressive symptom. Such compounds are particularly advantageous in thatthey have a low risk of opioid dependence, opioid addiction and orsymptoms of opioid withdrawal.

Accordingly, in certain embodiments of Formulas (I), (Ia), (Ib), (Ic),(II), (IIa), (III), (IV), (IVa), or (V), provided herein is a compoundthat is a μ opioid receptor to agonist having an Emax of 5% to 45%(e.g., 5, 10, 15, 20, 25, 30, 35, 40, or 45%) in a GTPγS binding assay.In one embodiment, the agonist exhibits an Emax of 15% to 35% in theGTPγS binding assay. In another embodiment, said agonist has a low riskof opioid dependence, opioid addiction and/or symptoms of opioidwithdrawal.

It has also been discovered that compounds eliciting a maximal dopamineefflux in the nucleus accumbens in a rat of 125% to 300% over base lineare particularly suitable for treating a depressive symptom. Suchcompounds are particularly advantageous in that they have a low risk ofopioid dependence, opioid addiction and/or symptoms of opioidwithdrawal.

Accordingly, in certain embodiments of Formulas (I), (Ia), (Ib), (Ic),(II), (IIa), (III), (IV), (IVa), or (V), provided here is a compoundthat exhibits a maximal dopamine efflux in the nucleus accumbens in arat of 125% to 300% (e.g., 125, 150, 175, 200, 225, 250, 275, or 300%)over base line. In one embodiment, the maximal dopamine efflux in thenucleus accumbens of a rat is 200% to 300% over base line.

It has further been discovered that compounds that do not attenuatethermal pain in a rodent hot plate model when administered at a dose ofat least 1 mg/kg (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg/kg) areparticularly suitable for treatment of a depressive symptom. Suchcompounds are particularly advantageous in that they have a low risk ofopioid dependence, opioid addiction and/or symptoms of opioidwithdrawal.

Accordingly, in certain embodiments of Formulas (I), (Ia), (Ib), (Ic),(II), (IIa), (III), (IV), (IVa), or (V), provided herein is a compoundthat does not attenuate thermal pain in a rodent hot plate model whenadministered at a dose of at least 1 mg/kg (e.g., 1, 2, 3, 4, 5, 6, 7,8, 9, or 10 mg/kg). In one embodiment, the compound does not attenuatethermal pain in a rodent hot plate model when administered at a dose of1-10 mg/kg (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/kg). In oneembodiment, the compound does not attenuate thermal pain in a rodent hotplate model when administered at a dose of at least 3 mg/kg. In anotherembodiment, the compound does not attenuate thermal pain in a rodent hotplate model when administered at a dose of 10 mg/kg. Such compounds areparticularly advantageous in that they have a low risk of opioiddependence, opioid addiction and/or symptoms of opioid withdrawal.

Methods of Treatment

The compounds of Formulas (I), (Ia), (Ib), (Ic), (II), (IIa), (III),(IV), (IVa), or (V), provided herein, are particularly suitable fortreating a depressive symptom. The depressive symptom can be depressedmood, loss of pleasure, loss of appetite, sleep disturbance, psychomotorchanges, fatigue, and/or post-partum depression. The depressive symptomcan be associated with a mental condition, wherein the mental conditionis schizoaffective disorder, and/or seasonal affective disorder.

The depressive symptom can be acute stress disorder, adjustmentdisorders with depressed mood, Asperger syndrome, attention deficit,bereavement, bipolar I disorder, bipolar II disorder, borderline andpersonality disorder, cyclothymia and dysthymia, depression such asmajor depressive disorder (MDD) and treatment-resistant disorder (TRD),Dysthymic disorder, hyperactivity disorder, impulse control disorder,mixed mania, obsessive-compulsive personality disorder (OCD), paranoid,post-traumatic stress disorder, seasonal affective disorder, self-injuryseparation, sleep disorder, substance-induced mood disorder, Tourettesyndrome and tic disorder, and/or Trichotillomania.

The depressive symptom can also be an anxiety disorder, wherein theanxiety disorder is generalized anxiety disorder, panic, agoraphobia,acute stress, and/or post-traumatic stress disorder.

The depressive symptom can be associated with chronic or recurrentdepression.

Accordingly, in one aspect, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formulas (I), (Ia), (Ib),(Ic), (II), (IIa), (III), (IV), (IVa), or (V), or a pharmaceuticallyacceptable salt thereof.

In one embodiment, provided herein is a method of treating a depressivesymptom in a subject in need thereof, comprising administering to thesubject the compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

In another embodiment, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formula (Ia) or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formula (Ib) or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formula (Ic) or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formula (II) or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formula (IIa) or apharmaceutically acceptable salt thereof.

In still another embodiment, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formula (III) or apharmaceutically acceptable salt thereof.

In yet another embodiment, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formula (IV) or apharmaceutically acceptable salt thereof.

In yet another embodiment, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formula (IVa) or apharmaceutically acceptable salt thereof.

In yet another embodiment, provided herein is a method of treating adepressive symptom in a subject in need thereof, comprisingadministering to the subject the compound of Formula (V) or apharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating depression ina subject in need thereof, comprising administering to the subject thecompound of Formulas (I), (Ia), (Ib), (Ic), (II), (IIa), (III), (IV),(IVa), or (V), or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method of treating depression ina subject in need thereof, comprising administering to the subject thecompound of Formula (I) or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treatingdepression in a subject in need thereof, comprising administering to thesubject the compound of Formula (Ia) or a pharmaceutically acceptablesalt thereof.

In another embodiment, provided herein is a method of treatingdepression in a subject in need thereof, comprising administering to thesubject the compound of Formula (Ib) or a pharmaceutically acceptablesalt thereof.

In another embodiment, provided herein is a method of treatingdepression in a subject in need thereof, comprising administering to thesubject the compound of Formula (Ic) or a pharmaceutically acceptablesalt thereof.

In another embodiment, provided herein is a method of treatingdepression in a subject in need thereof, comprising administering to thesubject the compound of Formula (II) or a pharmaceutically acceptablesalt thereof.

In another embodiment, provided herein is a method of treatingdepression in a subject in need thereof, comprising administering to thesubject the compound of Formula (IIa) or a pharmaceutically acceptablesalt thereof.

In still another embodiment, provided herein is a method of treatingdepression in a subject in need thereof, comprising administering to thesubject the compound of Formula (III) or a pharmaceutically acceptablesalt thereof.

In yet another embodiment, provided herein is a method of treatingdepression in a subject in need thereof, comprising administering to thesubject the compound of Formula (IV) or a pharmaceutically acceptablesalt thereof.

In yet another embodiment, provided herein is a method of treatingdepression in a subject in need thereof, comprising administering to thesubject the compound of Formula (IVa) or a pharmaceutically acceptablesalt thereof.

In yet another embodiment, provided herein is a method of treatingdepression in a subject in need thereof, comprising administering to thesubject the compound of Formula (V) or a pharmaceutically acceptablesalt thereof.

In one specific embodiment, provided herein is a method of treatingdepression and/or a depressive symptom in a subject in need thereof,comprising administering to the subject the compound:

or a pharmaceutically acceptable salt thereof.

It has been discovered that Emax value in a GTPγS binding assay can beused to select μ opioid receptor agonists for treatment of a depressivesymptom. In particular, it has been discovered that compounds with anEmax of 5% to 45% in a GTPγS binding assay are especially suitable fortreating depressive symptoms. Thus, in another aspect, provided hereinis a method of treating a depressive symptom in a subject in needthereof comprising administering to the subject an effective amount of aμ opioid receptor agonist that exhibits an Emax of 5% to 45% (e.g., 5,10, 15, 20, 25, 30, 35, 40, or 45%) in a GTPγS binding assay. In aparticular embodiment, the Emax of the agonist is 15% to 35% in theGTPγS binding assay. In another embodiment, the agonist has a low riskof opioid dependence, opioid addiction and or symptoms of opioidwithdrawal. Non-limiting examples of such a μ opioid receptor agonistsare the compounds of Formulas (I), (Ia), (Ib), (Ic), (II), (IIa), (III),(IV), (IVa), and (V).

It has also been discovered that a compound that exhibits a maximaldopamine efflux in the nucleus accumbens in a rat of 125% to 300% overbase line is particularly suitable for treatment of depressive symptoms.Thus, in another aspect, provided herein is a method of treating adepressive symptom in a subject in need thereof comprising administeringto the subject an effective amount of a compound that exhibits a maximaldopamine efflux in the nucleus accumbens in a rat of 125% to 300% (e.g.,125, 150, 175, 200, 225, 250, 275, or 300%) over base line. Inparticular embodiments, the maximal dopamine efflux in the nucleusaccumbens in a rat is 200% to 300% over base line. Non-limiting examplesof such compounds are the compounds of Formulas (I), (Ia), (Ib), (Ic),(II), (IIa), (III), (IV), (IVa), and (V).

In still another aspect, provided herein is a method of treating adepressive symptom in a subject in need thereof comprising administeringto the subject an effective amount of a compound that does not attenuatethermal pain in a rodent hot plate model when administered at of dose ofat least 1 mg/kg (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/kg). In oneembodiment, the compound does not attenuate thermal pain in a rodent hotplate model when administered at a dose of 1-10 mg/kg (e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or 10 mg/kg). In one embodiment, the compound does notattenuate thermal pain in a rodent hot plate model when administered ata dose of at least 3 mg/kg. In another embodiment, the compound does notattenuate thermal pain in a rodent hot plate model when administered ata dose of 10 mg/kg. Non-limiting examples of such a μ opioid receptoragonists are the compounds of Formulas (I), (Ia), (Ib), (Ic), (II),(IIa), (III), (IV), (IVa), and (V).

In certain embodiments of the methods described above, the depressivesymptom is depressed mood, loss of pleasure, loss of appetite, sleepdisturbance, psychomotor changes, fatigue, and/or post-partumdepression.

In another embodiment, the depressive symptom is associated with amental condition, wherein the mental condition is schizoaffectivedisorder, and/or seasonal affective disorder.

In still another embodiment, the depressive symptom is acute stressdisorder, adjustment disorders with depressed mood, Asperger syndrome,attention deficit, bereavement, bipolar I disorder, bipolar II disorder,borderline and personality disorder, cyclothymia and dysthymia,depression such as major depressive disorder (MDD) andtreatment-resistant disorder (TRD), Dysthymic disorder, hyperactivitydisorder, impulse control disorder, mixed mania, obsessive-compulsivepersonality disorder (OCD), paranoid, post-traumatic stress disorder,seasonal affective disorder, self-injury separation, sleep disorder,substance-induced mood disorder, Tourette syndrome and tic disorder,and/or Trichotillomania.

In yet another embodiment, the depressive symptom is an anxietydisorder, wherein the anxiety disorder is generalized anxiety disorder,panic, agoraphobia, acute stress and/or post-traumatic stress disorder.In another embodiment, the depressive symptom is associated with chronicor recurrent depression.

In another aspect, provided herein is a method of treating a disease orcondition associated with the group consisting of pain, pruritis,diarrhea, irritable bowel syndrome, gastrointestinal motility disorder,obesity, respiratory depression, convulsions, coughing, hyperalgesia,and drug addiction in a subject comprising administering to the subjecta pharmaceutical composition comprising the compound of Formulas (I),(Ia), (Ib), (Ic), (II), (IIa), (III), (IV), (IVa), or (V) as definedabove, or a pharmaceutically acceptable salt thereof.

In one embodiment, the drug addiction is selected from heroin, cocaine,nicotine, amphetamine and alcohol addiction.

In a further aspect, the invention is a method of treating a disease orcondition in a subject by altering a response mediated by an opioidreceptor comprising bringing into contact with the opioid receptor aneffective amount of the compound of Formulas (I), (Ia), (Ib), (Ic),(II), (IIa), (III), (IV), (IVa), or (V) as defined above.

In preferred embodiments of the methods described above, the subject isa human.

Definitions

The term “treat,” “treated,” “treating” or “treatment” includes thediminishment or alleviation of at least one symptom associated or causedby the state, disorder or disease being treated. In certain embodiments,the treatment comprises bringing into contact with the opioid receptoran effective amount of a μ opioid receptor agonist, such as a compoundof Formulas (I), (Ia), (Ib), (Ic), (II), (IIa), (III) or (IV), (IVa), or(V).

The term “subject” is intended to be a mammal Examples of subjectsinclude humans, dogs, cows, horses, pigs, sheep, goats, cats, mice,rabbits, rats, and transgenic non-human animals. In preferredembodiments, the subject is a human, e.g., a human suffering from adepressive symptom, pain, pruritis, diarrhea, irritable bowel syndrome,gastrointestinal motility disorder, obesity, respiratory depression,convulsions, coughing, hyperalgesia, or drug addiction.

As used to herein, the term “GTPγS binding assay” refers to the GTPγSbinding assay described in Example B1, herein. This GTPγS binding assayis performed under conditions such that the observed Emax value forbuprenorphine (CAS#52485-79-7) in this assay is at least 50% compared tobaseline.

As used to herein, the term “Emax” refers to the maximal observed effectof a compound. In certain embodiments, the Emax is the maximalpercentage increase of [35S]GTPγS binding induced by an agonist relativeto basal [35S]GTPγS binding in the absence of any drug.

As used to herein, the term “EC50” refers to the concentration of acompound required to achieve an effect that is 50% of the Emax.

As used to herein, the term “rodent hot plate model” refers to thethermal pain assay described in Example B2, herein.

As used herein the term “low risk of opioid dependence, opioid addictionand or symptoms of opioid withdrawal” refers to low “abuse liability.”Drugs with “abuse liability” are those associated with physical and/orpsychological dependence in humans, or with a probability for diversionfrom the intended medical condition for recreational use. There are avariety of animal models that can be used to assess the abuse liabilityof drugs. In general, these models use comparator drugs with known highabuse potential. For the opioid class of compounds, the most commoncomparator drug is morphine. Morphine has been shown clinically to havea high potential for abuse. Morphine produces a “drug high,” dependencywhen the drug is repeatedly administered, and withdrawal when the druguse is abruptly stopped. Each of these traits can be evaluated in animalmodels for a given experimental drug to determine its relative riskcompared to morphine. For example, efflux of nucleus accumbens dopaminecan be evaluated as a predictor of the high or euphoria followingadministration of the drug. A reduction in the maximal possible observedincrease in dopamine efflux would be correlated with a significantlylower degree of euphoria and a reduction in the abuse liabilityassociated with drug-liking. Similarly, the potential for dependence andwithdrawal can be determined in standard animal models in which the drugis administer 1-3 times per day, or by continual infusion for 5 to 14days, followed by abrupt withdrawal. For addictive opioids, abruptcessation of administration of the drug will cause withdrawalcharacterized by such traits as weight-loss associated with excessiveurination and defecation, increased shaking behavior, increased“jumping” activity, and reduced body temperature. These are quantitativemeasures that can be used to evaluate the relative risk for dependencycompared to morphine. The ability of a drug to induce withdrawal inopioid-dependent patients will also lead to a reduced abuse liabilityassociated with diversion of the drug. This feature can also be directlyassessed in animals by making them dependent on morphine, or anotheropioid agonist, and then precipitating withdrawal by the administrationof the drug. In certain embodiments, the compounds disclosed herein havea lower abuse liability (e.g., a lower risk of opioid dependence, opioidaddiction and or symptoms of opioid withdrawal) than buprenorphine.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 20carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 7 carbon atoms, 1 to 6 carbons, 1 to 4 carbons, or 1 to 3carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, n-decyl and the like. Furthermore, the expression“C_(x)-C_(y)-alkyl”, wherein x is 1-5 and y is 2-10 indicates aparticular alkyl group (straight- or branched-chain) of a particularrange of carbons. For example, the expression C₁-C₄-alkyl includes, butis not limited to, methyl, ethyl, propyl, butyl, isopropyl, tert-butyland isobutyl.

The term “alkenyl,” alone or in combination refers to a straight-chain,cyclic or branched hydrocarbon residue comprising at least one olefinicbond and the indicated number of carbon atoms. Preferred alkenyl groupshave up to 8, preferably up to 6, particularly preferred up to 4 carbonatoms. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl,1-cyclohexenyl, 1-cyclopentenyl.

As used herein, the term “cycloalkyl” or “carbocyclic” refers tosaturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbongroups of 3-12 carbon atoms, preferably 3-9, or 3-7 carbon atoms.Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups includebornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

“Alkoxyalkyl” refers to a group having the formula —R^(i)—OR^(ii),wherein R^(i) is an alkyl group as defined above, and OR^(ii) is analkoxy group as defined below.

“Alkoxy” refers to those alkyl groups, having from 1 to 10 carbon atoms,attached to the remainder of the molecule via an oxygen atom. Alkoxygroups with 1-8 carbon atoms are preferred. The alkyl portion of analkoxy may be linear, cyclic, or branched, or a combination thereof.Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, butoxy,cyclopentyloxy, and the like. An alkoxy group can also be represented bythe following formula: —OR^(i), where R^(i) is the “alkyl portion” of analkoxy group.

The term “hydroxyalkyl” refers to a group having the formula —R^(ii)—OH,wherein R^(ii) is an alkyl group as defined above.

The term “aryl” includes aromatic monocyclic or multicyclic e.g.,tricyclic, bicyclic, hydrocarbon ring systems consisting only ofhydrogen and carbon and containing from six to nineteen carbon atoms, orsix to ten carbon atoms, where the ring systems may be partiallysaturated. Aryl groups include, but are not limited to, groups such asphenyl, tolyl, xylyl, anthryl, naphthyl and phenanthryl. Aryl groups canalso be fused or bridged with alicyclic or heterocyclic rings which arenot aromatic so as to form a polycycle (e.g., tetralin).

The term “heteroaryl,” as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle” or “heterocyclyl” refers to a five-member toten-member, fully saturated or partially unsaturated nonaromaticheterocylic groups containing at least one heteroatom such as O, S or N.The most frequent examples are piperidinyl, morpholinyl, piperazinyl,pyrrolidinyl or pirazinyl. Attachment of a heterocyclyl substituent canoccur via a carbon atom or via a heteroatom.

Moreover, the alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl,heteroaryl, and heterocycle groups described above can be“unsubstituted” or “substituted.” The term “substituted” is intended todescribe moieties having substituents replacing a hydrogen on one ormore atoms, e.g. C, O or N, of a molecule. Such substituents canindependently include, for example, one or more of the following:straight or branched alkyl (preferably C₁-C₅), cycloalkyl (preferablyC₃-C₈), alkoxy (preferably C₁-C₆), thioalkyl (preferably C₁-C₆), alkenyl(preferably C₂-C₆), alkynyl (preferably C₂-C₆), heterocyclic,carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl(e.g., benzyl), aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl,alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other suchacyl group, heteroarylcarbonyl, or heteroaryl group, (CR′R″)₀₋₃NR′R″(e.g., —NH₂), (CR′R″)₀₋₃CN (e.g., —CN), —NO₂, halogen (e.g., —F, —Cl,—Br, or −I), (CR′R″)₀₋₃C(halogen)₃ (e.g., -CF₃), (CR′R″)₀₋₃CH(halogen)₂,(CR′R″)₀₋₃CH₂(halogen), (CR′R″)₀₋₃CONR′R″, (CR′R″)₀₋₃(CNH)NR′R″,(CR′R″)₀₋₃S(O)₁₋₂NR′R″, (CR′R″)₀₋₃CHO, (CR′R″)₀₋₃O(CR′R″)₀₋₃H,(CR′R″)₀₋₃S(O)₀₋₃R′ (e.g., —SO₃H, —OSO₃H), (CR′R″)₀₋₃O(CR′R″)₀₋₃H (e.g.,—CH₂OCH₃ and —OCH₃), (CR′R″)₀₋₃S(CR′R″)₀₋₃H (e.g., —SH and —SCH₃),(CR′R″)₀₋₃OH (e.g., —OH), (CR′R″)₀₋₃COR′, (CR′R″)₀₋₃(substituteed orunsubstituted phenyl), (CR′R″)₀₋₃(C₃-C₈ cycloalkyl), (CR′R″)₀₋₃CO₂R′(e.g., —CO₂H), or (CR′R″)₀₋₃OR′ group, or the side chain of anynaturally occurring amino acid; wherein R′ and R″ are each independentlyhydrogen, a C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, or aryl group.

As used herein, the term “acyl” refers to an organic radical linked to acarbonyl.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences,17.sup.th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 andJournal of Pharmaceutical Science, 66, 2 (1977), each of which isincorporated herein by reference in its entirety.

The description of the disclosure herein should be construed incongruity with the laws and principals of chemical bonding. For example,it may be necessary to remove a hydrogen atom in order accommodate asubstitutent at any given location. Furthermore, it is to be understoodthat definitions of the variables (i.e., “R groups”), as well as thebond locations of the generic formulae of the invention (e.g., FormulasI, Ia, Ib, Ic, II, IIa, III, IV, IVa, or V), will be consistent with thelaws of chemical bonding known in the art. It is also to be understoodthat all of the compounds of the invention described above will furtherinclude bonds between adjacent atoms and/or hydrogens as required tosatisfy the valence of each atom. That is, bonds and/or hydrogen atomsare added to provide the following number of total bonds to each of thefollowing types of atoms: carbon: four bonds; nitrogen: three bonds;oxygen: two bonds; and sulfur: two-six bonds.

The compounds of this invention may include asymmetric carbon atoms. Itis to be understood accordingly that the isomers arising from suchasymmetry (e.g., all enantiomers, stereoisomers, rotamers, tautomers,diastereomers, or racemates) are included within the scope of thisinvention. Such isomers can be obtained in substantially pure form byclassical separation techniques and by stereochemically controlledsynthesis. Furthermore, the structures and other compounds and moietiesdiscussed in this application also include all tautomers thereof.Compounds described herein may be obtained through art recognizedsynthesis strategies.

It will also be noted that the substituents of some of the compounds ofthis invention include isomeric cyclic structures. It is to beunderstood accordingly that constitutional isomers of particularsubstituents are included within the scope of this invention, unlessindicated otherwise. For example, the term “tetrazole” includestetrazole, 2H-tetrazole, 3H-tetrazole, 4H-tetrazole and 5H-tetrazole.

Pharmaceutical Compositions

The compounds of the present invention are suitable as active agents inpharmaceutical compositions that are efficacious particularly fortreating a depressive symptom, e.g. depressed mood, loss of pleasure,loss of appetite, sleep disturbance, psychomotor changes, fatigue, orpost-partum depression, or combinations thereof. The compounds of thepresent invention are also suitable as active agents in pharmaceuticalcompositions that are efficacious particularly for treating pain,pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motilitydisorder, obesity, respiratory depression, convulsions, coughing,hyperalgesia, and/or drug addiction. The pharmaceutical composition invarious embodiments has a pharmaceutically effective amount of thepresent active agent along with other pharmaceutically acceptableexcipients, carriers, fillers, diluents and the like.

The language “pharmaceutically effective amount” or “pharmaceuticallyacceptable amount” of the compound is that amount necessary orsufficient to treat the corresponding disease or condition, e.g.treating a depressive symptom in a subject in need of, or treating in asubject in need of a disease or condition associated with pain,pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motilitydisorder, obesity, respiratory depression, convulsions, coughing,hyperalgesia, or drug addiction, or combinations thereof. In an example,an effective amount of a compound of the invention is the amountsufficient to alter a response of an opioid receptor in a subject. Theeffective amount can vary depending on such factors as the size andweight of the subject, the type of illness, or the particular compoundof the invention. For example, the choice of the compound of theinvention can affect what constitutes an “effective amount.” One ofordinary skill in the art would be able to study the factors containedherein and make the determination regarding the effective amount of thecompounds of the invention without undue experimentation.

The regimen of administration can affect what constitutes apharmaceutically effective amount. A compound of the invention can beadministered to the subject either prior to or after the onset of adisease or condition provided herein. Further, several divided dosages,as well as staggered dosages can be administered daily or sequentially,or the dose can be continuously infused, or can be a bolus injection.Further, the dosages of the compound(s) of the invention can beproportionally increased or decreased as indicated by the exigencies ofthe therapeutic or prophylactic situation.

In one non-limiting embodiment, the phrase “pharmaceutically effectiveamount” refers to the amount of a compound of the present inventionthat, when administered to a subject, is effective to (1) at leastpartially alleviate, inhibit, prevent and/or ameliorate a condition, ora disorder or a disease mediated by an opioid receptor, or (2) alteringa response of an opioid receptor. In another non-limiting embodiment,the phrase “pharmaceutically effective amount” refers to the amount of acompound of the present invention that, when administered to a subject,is effective to at least partially alleviate, inhibit, prevent and/orameliorate a depressive symptom, such as depressed mood, loss ofpleasure, loss of appetite, sleep disturbance, psychomotor changes,fatigue, and/or post-partum depression. In still another non-limitingembodiment, the term “pharmaceutically effective amount” refers to theamount of a compound of the present invention that, when administered toa subject, at least partially alleviate, inhibit, prevent and/orameliorate a disease or condition associated with the group consistingof pain, pruritis, diarrhea, irritable bowel syndrome, gastrointestinalmotility disorder, obesity, respiratory depression, convulsions,coughing, hyperalgesia, and/or drug addiction.

The effective amount can vary depending on such factors as the size andweight of the subject, the type of illness, or the particular organiccompound. For example, the choice of the organic compound can affectwhat constitutes an “effective amount.” One of ordinary skill in the artwould be able to study the aforementioned factors and make thedetermination regarding the acceptable amount of the organic compoundwithout undue experimentation.

Compounds of the invention may be used in the treatment of states,disorders or diseases as described herein, or for the manufacture ofpharmaceutical compositions for use in the treatment of these diseases.

The language “pharmaceutical composition” includes preparations suitablefor administration to mammals, e.g., humans. When the compounds of thepresent invention are administered as pharmaceuticals to mammals, e.g.,humans, they can be given per se or as a pharmaceutical compositioncontaining, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) ofactive ingredient in combination with a pharmaceutically acceptablecarrier.

The phrase “pharmaceutically acceptable carrier” is art recognized andincludes a pharmaceutically acceptable material, composition or vehicle,suitable for administering compounds of the present invention tomammals. The carriers include liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting the subject agent from one organ, or portion of the body,to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the patient. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, a-tocopherol, and the like; and metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteraladministration. The formulations may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amount of active ingredient that can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound that produces a therapeutic effect. Generally,out of one hundred per cent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably fromabout 5 per cent to about 70 per cent, most preferably from about 10 percent to about 30 per cent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluent commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc., administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral and/or IV administration is preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous and subcutaneousdoses of the compounds of this invention for a patient, when used forthe indicated analgesic effects, will range from about 0.0001 to about100 mg per kilogram of body weight per day, more preferably from about0.01 to about 50 mg per kg per day, and still more preferably from about1.0 to about 100 mg per kg per day. An effective amount is that amounttreats a protein kinase-associated disorder.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical composition.

Exemplification of the Invention

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The practice of the presentinvention will employ, unless otherwise indicated, conventionaltechniques of cell biology, cell culture, molecular biology, transgenicbiology, microbiology and immunology, which are within the skill of theart.

Part A. Synthetic Procedures

Synthesis procedures for preparation of the compounds of the inventionare readily available to the ordinary skilled artisan. For example,

U.S. Pat. No. 7,262,298 and PCT publication WO2012/088494 illustratesynthesis methods for the compounds of Formulas (I), (Ia), (Ib), and(Ic), which are morphinan analogues;

U.S. Pat. No. 8,252,929 provides synthesis methods for the compounds ofFormulas (II) and (IIa), which are morphan analogues;

U.S. Pat. No. 8,026,252 provides synthesis methods for the compounds ofFormula (III), which are morphan and morphinan analogues with largesubstituents attached to the phenyl;

Neumeyer et al. (Journal of Med. Chem. 2012, p 3878) shows exemplarysynthesis methods for the compounds of Formulas (IV) and (Iva), whichare morphinan analogues and can have a —NH—CH₂-phenyl substitution groupon the phenyl; and

U.S. Pat. No. 8,252,929 provides synthesis methods for the compounds ofFormula (V), which are morphine analogues.

All of the above-referenced patents and literatures are incorporatedherein by reference in their entirety.

General Procedure to Synthesize a NH Core Compound Synthesis of(4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-ol

To Hydromorphone HCl (15.0 g, 46 7 mmol) was added ethylene glycol (80mL) and methane sulfonic acid (10 mL) and the reaction heated at 80° C.overnight. The reaction was cooled to room temperature and poured intoice/NH_(3(aq)) (˜350 mL). The product was extracted with dichloromethaneand dried over MgSO₄ before concentration under reduced pressure to give(4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-ol(19 g, 99.9% LCMS); [M+H]⁺330.5. This was taken onto the next stepwithout purification.

Synthesis of(4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-yl trifluoromethanesulfonate

To a mixture of(4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-ol(21.54 g, 46.73 mmol) and triethylamine (20 mL, 140.2 mmol) indichloromethane (600 mL) was addedN-Phenylbis(trifluoromethanesulfonamide) (17.53 g, 49.0 mmol) and themixture stirred at room temperature overnight. The solvent wasconcentrated under reduced pressure and the residue taken up in 20%hexane in ethyl acetate (1 L) and washed with water (×5). The organicphase was dried (MgSO₄). Filtration and removal of the solvent underreduced pressure gave(4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-yltrifluoromethanesulfonate(20.77 g, 96% pure LCMS); [M+H]⁺462.1.

Synthesis of(4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile

To a solution of(4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-yltrifluoromethanesulfonate (20.77 g, 45.0 mmol) in degasseddimethylformamide (400 mL) was addedtetrakis(triphenylphosphine)palladium(0) (5.21 g, 4.50 mmol). Afterheating to 40° C., zinc cyanide (3.18 g, 27.0 mmol) was added and thereaction mixture heated at 110° C. for 6 hours. The reaction mixture wascooled to room to temperature and diluted with ethyl acetate andfiltered through a pad of celite. The filtrate was diluted further withethyl acetate and washed with water (3×500 mL). The aqueous phase wasbasified with sodium hydrogen carbonate solution and re-extracted withethyl acetate and the combined organics dried (MgSO₄), filtered andconcentrated under reduced pressure. Purification by silicachromatography (100% dichloromethane to 5% NH₃/methanol indichloromethane) gave(4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile(10.0 g, 91% pure LCMS, 63% yield over three steps); [M+H]⁺339.1.

Synthesis of(4R,4aR,7aR,12bS)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile

To a suspension of(4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile(5.0 g, 17 8 mmol) in dimethylformamide (50 mL) was added diisopropylazodicarboxylate (5.4 mL, 27.5 mmol). The reaction was heated to 55° C.for 3 hours until the starting material was consumed. To the reactionwas added dimedone (5.8 g, 41.4 mmol) and methanol (1.75 mL, 54.8 mmol)and the reaction heated to 60° C. for 3 hours. The reaction was allowedto cool to room temperature and poured into 0.5 M HCl_((aq)) (50 mL).The aqueous phase was washed with diethyl ether: ethyl acetate (3:1).The organic phase was back extracted with 0.5 M HCl_((aq)) and acidicphases combined before basifying with 2M NaOH until pH9. The aqueousphase was extracted with ethyl acetate (×3). The combined organic phaseswere washed with water/brine (×3) before drying over MgSO₄ andconcentrating under reduced pressure. The residue was purified by silicachromatography (5% methanol in dichloromethane to 5% NH₃/methanol indichloromethane) to give(4R,4aR,7aR,12bS)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrileas a pale yellow solid (3.90 g, 95% pure LCMS, 81% yield); [M+H]⁺325.1.

General Procedure to Synthesize a Deoxygenated Core Compound Synthesisof(4R,4aR,7aR,12bS)-9-(benzyloxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one

To Hydromorphone HCl (50.0 g, 155.3 mmol) in dimethylformamide (500 mL)was added sodium hydride (14.30 g, 357.4 mmol) portionwise with cooling.The addition was conducted over 25 minutes. The reaction was stirred atroom temperature for 1.5 hours before the addition of benzyl chloride(17.88 mL, 357.4 mmol) over 10 minutes with cooling. The reaction wasallowed to warm to room temperature and stirred for 40 hours. Thereaction was incomplete so additional benzyl chloride (1.79 mL, 15.5mmol) was added. After 4 hours, the reaction was quenched with water (60mL), acidified with aqueous HCl (2M, 800 mL) and washed with ethylacetate/diethyl ether (3:1) (2×800 mL). The aqueous phase was basifiedwith aqueous NaOH (2M, 800 mL) and extracted with ethyl acetate (2×1 L).The organic phases were combined, washed with water/brine (1:1) (2×800mL) and dried over MgSO₄ before concentration under reduced pressure.The residue was taken up in ethyl acetate and washed with water/brine(2×500 mL), dried over MgSO₄ before concentration under reduced pressureto give(4R,4aR,7aR,12bS)-9-(benzyloxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(47.9 g, 95% pure by NMR, 82% yield); [M+H]⁺376.2. This was taken ontothe next step without purification.

Synthesis of(4bS,8aR,9R)-3-(benzyloxy)-4-hydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

To(4R,4aR,7aR,12bS)-9-(benzyloxy)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(58.32 g, 0.16 mol) in ethanol (1.55 L) was added ammonium chloride(124.65 g, 2.33 mol) and zinc powder (101.59 g, 1.55 mol). The reactionwas heated to reflux and monitored by TLC. Once complete, the reactionwas allowed to cool and filtered through a pad of celite. The pad waswashed thoroughly with ethanol (1 L) and methanol (1 L). The filtratewas concentrated under reduced pressure. The residue was taken up indichloromethane and aqueous ammonia (˜15%, 1 L) before the product wasextracted with dichloromethane (3×700 mL). The dichloromethane phaseswere combined, washed with brine and dried over MgSO₄ before beingconcentrated under reduced pressure. The residue was purified by silicachromatography eluted with 10% methanol, 5% Et₃N in dichloromethane togive(4bS,8aR,9R)-3-(benzyloxy)-4-hydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(50.4 g, 74.3% pure LCMS, 64% yield); [M+H]⁺378.2.

Synthesis of(4bS,8aR,9R)-3-(benzyloxy)-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yltrifluoromethanesulfonate

To a solution of(4bS,8aR,9R)-3-(benzyloxy)-4-hydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(28.2 g, 74 7 mmol) in tetrahydrofuran under an atmosphere of argon at0° C. was added sodium hydride (4.48 g, 112.1 mmol) portionwise. Thereaction was stirred for 30 minutes beforeN-Phenylbis(trifluoromethanesulfonamide) (40.03 g, 112.1 mmol) wasadded. The reaction was left to warm to room temperature overnight. Thereaction was cooled to 0° C. and quenched with IPA followed by water.The solution was diluted with ethyl acetate/heptanes (1:1) and aqueousammonia (30%, 400 mL) added. The phases were separated and the organicphase washed with aqueous ammonia (15%) twice before being washed withbrine, dried over MgSO₄ and concentrated under reduced pressure. Theresidue was purified by silica chromatography eluted with a gradientfrom 2.5-10% methanol/dichloromethane to give(4bS,8aR,9R)-3-(benzyloxy)-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yltrifluoromethanesulfonate (31.6 g, 81% pure LCMS, 67% yield);[M+H]⁺510.2.

Synthesis of(4bS,8aR,9R)-3-(benzyloxy)-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one

To a solution of(4bS,8aR,9R)-3-(benzyloxy)-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yltrifluoromethanesulfonate(31.9 g, 62.6 mmol) in degassed dimethylformamide (320 mL) was addedPd(OAc)₂ (1.405 g, 6.6 mmol), 1,3-bis(diphenylphosphino)propane (2.58 g,6.3 mmol) and triethylsilane (100 mL, 626.0 mmol). The reaction washeated to 86° C. under argon for 4 hours. The reaction was cooled toroom temperature, quenched with 2M HCl and extracted with diethyl ether:ethyl acetate (1:1). The organic phase was washed with 2M HCl. The acidphases were combined and washed with diethyl ether:ethyl acetate (1:1)(×3). The aqueous phase was basified with 2M NaOH and extracted withethyl acetate (×3). The organic phase was washed with water (×3) andthen brine before being dried over MgSO₄ and concentrated under reducedpressure to give(4bS,8aR,9R)-3-(benzyloxy)-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(20.2 g, 85% pure LCMS); [M+H]⁺362.3. This was taken onto the next stepwithout purification.

Synthesis of (4bS,8aR,9R)-3-(benzyloxy)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]

To a suspension of(4bS,8aR,9R)-3-(benzyloxy)-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(20.2 g, 55 9 mmol) in ethylene glycol (280 mL) was added methanesulfonic acid (14.5 mL, 223.5 mmol). The reaction went into solution andwas stirred at room temperature for 16 hours. The reaction was pouredinto aqueous ammonia/ice and was extracted with ethyl acetate (×3). Theorganics were combined, washed with water/brine (×3) and dried overMgSO₄ and concentrated under reduced pressure to give(4bS,8aR,9R)-3-(benzyloxy)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane](18.6 g, 84% pure UPLC); [M+H]⁺406.3. This was taken onto the next stepwithout purification.

Synthesis of(4bS,8aR,9R)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolan]-3-ol

To a solution of(4bS,8aR,9R)-3-(benzyloxy)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane](21.8 g, 53.8 mmol) in ethanol (545 mL) was added 10% palladium oncarbon (2.2 g, 0.1 eq by weight) and the reaction placed under anatmosphere of hydrogen. The reaction was stirred for 16 hours at roomtemperature. The reaction was filtered through a pad of celite and thefiltrate concentrated under reduced pressure to give(4bS,8aR,9R)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolan]-3-ol(16.9 g, 73% pure LCMS); [M+H]⁺316.2. This was taken onto the next stepwithout purification.

Synthesis of(4bS,8aR,9R)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolan]-3-yltrifluoromethanesulfonate

To a mixture of(4bS,8aR,9R)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolan]-3-ol(16.95 g, 53.7 mmol) and triethylamine (22.5 mL, 161 2 mmol) indichloromethane (400 mL) was addedN-Phenylbis(trifluoromethanesulfonamide) (19.77 g, 55 4 mmol) and themixture stirred at room temperature overnight. The solvent wasconcentrated under reduced pressure and the residue taken up in ethylacetate. The organic phase was washed with aqueous ammonia/water (1:1×3)before washing with brine. The organic phase was dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by silicachromatography eluted with 0-10% methanol in dichloromethane to give(4bS,8aR,9R)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolan]-3-yltrifluoromethanesulfonate (18.7 g, 76.8% pure LCMS, 57.7% over 4steps,); [M+H]⁺448.2.

Synthesis of(4bS,8aR,9R)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile

To a solution of(4bS,8aR,9R)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolan]-3-yltrifluoromethanesulfonate (18.7 g, 41.8 mmol) in degasseddimethylformamide (250 mL) was addedtetrakis(triphenylphosphine)palladium(0) (4.83 g, 4.2 mmol). Afterheating to 40° C., zinc cyanide (2.94 g, 25 0 mmol) was added and thereaction mixture heated at 130° C. for 24 hours. Reaction incomplete socooled to room temperature and tetrakis(triphenylphosphine)palladium(0)(4.83 g, 4 2 mmol) was added and the reaction heated to 135° C. for 4hours. The reaction mixture was cooled to room temperature and dilutedwith ethyl acetate and quenched with sodium hydrogen carbonate solution.The mixture was filtered through a pad of celite. The phases wereseparated and the product extracted with ethyl acetate (×3). The organicphases were combined, washed with water/brine (×3), dried over MgSO₄ andconcentrated under reduced pressure. Purification by silicachromatography (100% dichloromethane to 5% NH₃/methanol indichloromethane) gave(4bS,8aR,9R)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile(8.26 g, 89% pure LCMS). [M+H]⁺325.2.

Synthesis of(4bS,8aR,9R)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile

To a suspension of(4bS,8aR,9R)-11-methyl-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile(8.26 g, 25 5 mmol) in dimethylformamide (65 mL) was added diisopropylazodicarboxylate (9.32 mL, 47.4 mmol). The reaction was heated to 55° C.for 4 hours until starting material is consumed. To the reaction wasadded dimedone (9.99 g, 71.3 mmol) and methanol (3.1 mL, 94 2 mmol) andthe reaction heated to 60° C. for 3 hours. The reaction was allowed tocool to room temperature overnight. The reaction was poured into 0.5 MHCl_((aq)) (250 mL) and washed with diethyl ether: ethyl acetate (3:1).The organic phase was back extracted with 0.5 M HCl_((aq)) (250 mL) andthe acidic phases combined before basifying with 2M NaOH until pH9. Theaqueous phase was extracted with ethyl acetate (×3). The combinedorganic phases were washed with water/brine (×3) before drying overMgSO₄ and concentrating under reduced pressure. The residue was purifiedby silica chromatography (100% dichloromethane to 10% NH₃/methanol indichloromethane) to give(4bS,8aR,9R)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile(5.95 g, 42% yield over two steps, 92% pure LCMS); [M+H]⁺311.2.

A1. Experimental Procedure for Compound A and a Hydrochloride SaltThereof:

2-Cyclobutanecarbaldehyde

To a mixture of Pyridinium chlorochromate (41.3 g, 191 6 mmol) indichloromethane (120 mL) was added Cyclobutanemethanol (7.5 g, 87.1mmol). The mixture was stirred for 1.5 hours then filtered through a padof silica and rinsed with further dichloromethane (300 mL). The solventwas removed under reduced pressure to give 2-cyclobutylcarbaldehyde(10.0 g, contains residual dichloromethane) that was used withoutfurther purification.

4R4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]lisoquinolin-7(7aH)-one

A mixture of Noroxymorphone (8.8 g, 30.6 mmol) in methanol (250 mL) wasdegassed for 20 minutes. 2-cyclobutanecarbaldehyde (7.7 g, 91 5 mmol)was added and the mixture heated at reflux for 1 hour. The reactionmixture was cooled to ambient temperature. In a separate flask formicacid (14.0 g, 306 mmol) was added slowly to a solution of triethylamine(12.4 g, 123 mmol) in methanol (40 mL). The formic acid solution wasstirred for 5 minutes before being added to the solution containingNoroxymorphone along with dichloro(p-cymene)ruthenium(II) dimer (53 mg).The reaction was heated at reflux for a further 2.5 hours. The reactionwas concentrated under reduced pressure then partitioned between ethylacetate and saturated sodium bicarbonate solution. The aqueous phase wasextracted with further ethyl acetate then the organic layers combinedand dried (MgSO₄). Filtration and removal of the solvent under reducedpressure gave(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(10.2 g, 94% yield); LC/MS (M+H)⁺=356.2.

(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yltrifluoromethanesulfonate

To a solution of(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(10.2 g, 28.7 mmol) and triethylamine (12.2 mL, 88 3 mmol) indichloromethane (200 mL) was addedN-Phenylbis(trifluoromethanesulfonamide) (11.0 g, 30. 9 mmol) and themixture stirred at room temperature overnight. The solvent wasconcentrated under reduced pressure and the residue partitioned between20% hexane in ethyl acetate (500 mL) and water (300 mL). The organiclayer was washed twice more with water and dried (MgSO₄). Filtration andremoval of the solvent under reduced pressure gave(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yltrifluoromethanesulfonate (14.3 g, 100% yield); LC/MS (M+H)⁺=488.1.

(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-N-(2,4-dimethoxybenzyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide

To a solution of(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yltrifluoromethanesulfonate (14.3 g, 29 3 mmol) in degassed dimethylsulfoxide (185 mL), was added N-hydroxysuccinimide (6.8 g, 58.7 mmol),palladium acetate (0.66 g, 2.93 mmol), triethylamine (8.2 mL, 58.7 mmol)and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.7 g, 2.93 mmol).The reaction mixture was heated with carbon monoxide (latm) at 75° C.overnight. The reaction mixture was cooled to ambient temperature and2,4-dimethoxybenzylamine (4.9 g, 29.3 mmol) added. The mixture wasstirred for 1 hour before partitioning between water (2 L) and ethylacetate (1 L). The aqueous phase was extracted twice more with ethylacetate. The combined organic phase was dried (MgSO₄), filtered, and thesolvent removed under reduced pressure. The crude material was purifiedby silica chromatography (3% methanol in dichloromethane) to give(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-N-(2,4-dimethoxybenzyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide(14.4 g, 55% yield); LC/MS (M+H)⁺=533.3.

(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide

A mixture of(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-N-(2,4-dimethoxybenzyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide(14.4 g, 27.0 mmol) in trifluoroacetic acid was stirred at ambienttemperature for 2 hours. The trifluoroacetic acid was removed underreduced pressure and the residue quenched with 300 mL of ammoniumhydroxide (6%). The product was extracted twice into dichloromethane(300 mL), the organic phases combined and dried (MgSO₄). Filtration andremoval of to the solvent under reduced pressure gave(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide(9.0 g, 87% yield); LC/MS (M+H)⁺=383.2.

(4bR,8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(Compound A)

To a mixture of(4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide(4.5 g, 11.8 mmol), and zinc powder (29.0 g, 444 mmol) in acetic acid(135 mL) was added conc. HCl (25.5 mL). The mixture was heated to 125°C. for 2 hours. The reaction mixture was cooled to ambient temperatureand quenched into ice/ammonium hydroxide solution (1 L, 28%). Theproduct was extracted into dichloromethane (1 L) and dried (MgSO₄).Filtration and removal of the solvent under reduced pressure gave thecrude material which was purified by silica chromatography (7.5%methanol/ammonia in DCM) followed by recrystallisation from methanol togive(4bR,8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(2.1 g, 46% yield); LC/MS (M+H)⁺=385.2.

4bR8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihdroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride

To a solution of(4bR,8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(2.1 g, 5.46 mmol) in ethyl acetate (100 mL) was added 2N HO/ether (6mL, 12 mmol) and the mixture stirred for 4 hours. The solvent wasremoved under reduced pressure and dried (55° C.) giving(4bR,8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride (2.25 g, 98% yield); LC/MS (M+H)⁺=385.2. ¹H-NMR (400 MHz,DMSO) 6 8.98 (br s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.68 (d, 1H), 6.64(d, 1H), 6.33 (s, 1H), 3.85 (d, 1H), 3.45 (br s, 1H), 3.29 (br s,3H+H₂O), 3.15-2.91 (m, 2H), 2.74-2.60 (m, 3H), 2.40-2.10 (m, 2H),2.12-1.55 (m, 10H).

A2. Experimental Procedure for Compound D and a Hydrochloride SaltThereof

4bR6R8aS,9R)-11-(cyclobutylmethyl)-4,6,8a-trihdro-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(Compound D)

A solution of formamidinesulfinic acid (1.12 g, 10.4 mmol, 4.00 eq.) in0.5 M aqueous sodium hydroxide (20 mL) was added dropwise over 10minutes to a stirred to solution of(4bR,8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide (1.00 g, 2.60 mmol, 1.00 eq.) in 0.5 NNaO_((aq)) (30 mL) at ambient temperature under argon. The mixture washeated to 80° C. under argon for 12 hours and then cooled to roomtemperature. The precipitated solid was collected by filtration and thenwashed with water (2×10 mL) and diethyl ether (2×20 mL). The solid wasrecrystallised in methanol and then dried at 50° C. under vacuum for 3hours to leave(4bR,6R,8aS,9R)-11-(cyclobutylmethyl)-4,6,8a-trihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamideas colourless crystals (400 mg, 40% yield); LC/MS (M+H)⁺=387.26.

(4bR,6R,8aS,9R)-11-(cyclobutylmethyl)-4,6,8a-trihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride

A solution of hydrochloric acid (0.40 mL, 2.0 M in diethyl ether) wasadded dropwise over 5 minutes to a stirred solution of(4bR,6R,8aS,9R)-11-(cyclobutylmethyl)-4,6,8a-trihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide (400 mg, 1.03 mmol, 1.00 eq.) in ethylacetate (4 mL) at ambient temperature under argon. The mixture wasstirred at ambient temperature under argon for 3 hours and thenconcentrated under reduced pressure. The solid was dried at 50° C. undervacuum for 1 hour, and then freeze dried to leave(4bR,6R,8aS,9R)-11-(cyclobutylmethyl)-4,6,8a-trihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride as a colourless solid (379 mg, 87%); LC/MS (M+H)⁺=387.26.¹H NMR (300 MHz, CDCl3, 614-181-1_(—)1H-1.jdf): 14.43 (s, 1H), 8.80 (br.s, 1H), 8.47 (s, 1H), 7.95 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 6.63 (d,J=8.3 Hz, 1H), 5.69 (s, 1H), 4.45 (s, 1H), 3.31-3.08 (m, 6H), 3.00-2.81(m, 2H), 2.70-2.57 (m, 1H), 2.40-2.23 (m, 1H), 2.17-1.91 (m, 3H),1.90-1.70 (m, 4H), 1.67-1.31 (m, 6H).

A3. Experimental Procedure for Compound C and a Hydrochloride SaltThereof:

(4bR,6S,8aS,9R)-11-(cyclobutylmethyl)-4,6,8a-trihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(Compound C)

A solution of K-selectride (7.80 mL, 7.80 mmol, 3.00 eq., 1.0 M intetrahydrofuran) was added dropwise over 15 minutes to a stirredsolution of(4bR,8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide (1.00 g, 2.60 mmol, 1.00 eq.) intetrahydrofuran(50 mL) at 0° C. under argon. The mixture was stirred at0° C. under argon for 2 hours and then water (20 mL) and methanol (50mL) were carefully added dropwise over 15 minutes. The mixture wasneutralised to pH 7 by addition of 2N HCl_((aq)). The mixture wasconcentrated under reduced pressure and the solid residue recrystallisedin methanol. The solid was washed with methanol (4 mL) and diethyl ether(2×10 mL), and then dried at 50° C. under vacuum for 3 hours to leave(4bR,6S,8aS,9R)-11-(cyclobutylmethyl)-4,6,8a-trihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamideas colourless crystals (750 mg, 74%); LC/MS (M+H)⁺=387.3.

4bR6S8c-trihdroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride

A solution of hydrochloric acid (0.75 mL, 2.0 M in diethyl ether) wasadded dropwise over 5 minutes to a stirred solution of(4bR,6S,8aS,9R)-11-(cyclobutylmethyl)-4,6,8a-trihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(750 mg, 1.94 mmol) in ethyl acetate (10 mL) at ambient temperatureunder argon. The mixture was stirred at ambient temperature under argonfor 3 hours and then concentrated under reduced pressure. The solid wastriturated with diethyl ether (2×10 mL), dried at 50° C. under vacuumfor 1 hour, then freeze dried to leave(4bR,6S,8aS,9R)-11-(cyclobutylmethyl)-4,6,8a-trihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride as a colourless solid (695 mg, 85% yield); LC/MS(M+H)⁺=387.3. ¹H NMR (300 MHz, DMSO): δ 14.26 (s, 1H), 8.82 (br. s, 1H),8.36 (s, 1H), 7.79 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 6.56 (d, J=8.3 Hz,1H), 5.63 (s, 1H), 3.83 (s, 1H), 3.63 (s, 1H), 3.49-3.36 (m, 1H),3.29-3.08 (m, 4H), 2.97-2.80 (m, 2H), 2.72-2.58 (m, 1H), 2.36-2.20 (m,1H), 2.14-1.70 (m, 9H), 1.68-1.49 (m, 2H), 1.38-1.22 (m, 2H).

A4. Experimental Procedure for:

2R,6R,11R)-tert-butyl8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate

A mixture of (-)-Normetazocine (5.0 g, 23 0 mmol), di-tert-butyldicarbonate to (7.53 g, 34.5 mmol), and sodium hydrogen carbonate (5.80g, 69.0 mmol), in dichloromethane (170 mL), tetrahydrofuran (170 mL),methanol (85 mL) and water (500 mL) was stirred at ambient temperatureovernight. The organic phase was separated and the aqueous phase washedtwice with dichloromethane (500 mL). The combined organic phases weredried (_(MgSO4))_(.) Filtration and removal of the solvent under reducedpressure gave oil that was dissolved in industrial methylated spirits(250 mL) and stirred with imidazole (3.0 g, 44.1 mmol) for 1 hour. Thesolvent was removed under reduced pressure and the residue partitionedbetween dichloromethane (250 mL) and 0.5N HCl_((aq)) (250 mL). Theorganic phase was washed with further acid (250 mL), brine (100 mL), anddried (MgSO₄). Filtration and removal of the solvent under reducedpressure gave (2R,6R,11R)-tert-butyl8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate(3.9 g, 53% yield); LC/MS(M+H)⁺=318.5.

(2R,6R,11R)-tert-butyl6,11-dimethyl-8-(((trifluoromethyl)sulfonyl)oxy)-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate

To a solution of (2R,6R,11R)-tert-butyl8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate(3.9 g, 12 3 mmol) and triethylamine (5.1 mL, 36 9 mmol) indichloromethane (100 mL) was addedN-Phenylbis(trifluoromethanesulfonamide) (4.61 g, 12 9 mmol) and themixture stirred to at ambient temperature for 4 hours. The solvent wasconcentrated under reduced pressure and the residue partitioned between20% hexane in ethyl acetate (500 mL) and water (400 mL). The organiclayer was washed four more times more with water and dried (MgSO₄).Filtration and removal of the solvent under reduced pressure gave(2R,6R,11R)-tert-butyl6,11-dimethyl-8-(((trifluoromethyl)sulfonyl)oxy)-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate(5.32 g, 96% yield); LC/MS (M+H)⁺=450.4.

(2R,6R,11R)-tert-butyl8-((2,4-dimethoxybenzyl)carbamoyl)-6,11-dimethyl-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate

To a solution of (2R,6R,11R)-tert-butyl6,11-dimethyl-8-(((trifluoromethyl)sulfonyl)oxy)-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate(5.32 g, 11 8 mmol) in degassed dimethyl sulfone (50 mL), was addedN-hydroxysuccinimide (2.73 g, 23.7 mmol), palladium acetate (265 mg,1.18 mmol), triethylamine (3.3 mL, 23 7 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (683 mg, 1.18 mmol). Thereaction mixture was heated with carbon monoxide (latm) at 70° C.overnight. The reaction mixture was cooled to ambient temperature and2,4-dimethoxybenzylamine (2.17 mg, 13.0 mmol) added. The mixture wasstirred for 2 hours diluted with ethyl acetate (800 mL), and filteredthrough celite. The organic solution was washed twice with water (800mL), brine (300 mL), and dried (MgSO₄). Filtration and removal of thesolvent under reduced pressure gave crude material that was purified bysilica chromatography (EtOAc(1):heptanes(1)) to give(2R,6R,11R)-tert-butyl84(2,4-dimethoxybenzyl)carbamoyl)-6,11-dimethyl-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate(4.0 g, 68% yield); LC/MS(M+H)⁺=495.3.

(2R,6R,11R)-N-(2,4-dimethoxybenzyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamidehydrochloride

A mixture of (2R,6R,11R)-tert-butyl8-((2,4-dimethoxybenzyl)carbamoyl)-6,11-dimethyl-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate(4.00 g, 8.09 mmol) in 4N HO/dioxane was stirred at ambient temperatureovernight. The majority of the solvent was decanted and the residuewashed with diethyl ether (500 mL). The resulting solid was dried underreduced pressure giving(2R,6R,11R)-N-(2,4-dimethoxybenzyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamidehydrochloride (3.35 g, 96% yield); LC/MS (M+H)⁺=395.5.

(2R,6R,11R)-N-(2,4-dimethoxybenzyl)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide

A mixture of2R,6R,11R)-N-(2,4-dimethoxybenzyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamidehydrochloride (400 mg, 0.93 mmol), potassium carbonate (385 mg, 2.78mmol), and bromoethyl methyl ether (142 mg, 1.02 mmol) in acetonitrile(15 mL) was heated at 65° C. overnight. Further bromoethyl methyl etherwas added (70 mg, 0.50 mmol) and the reaction heated at 65° C. for 24hours. The reaction mixture was allowed to return to ambient temperaturebefore partitioning between ethyl acetate (100 mL) and water (100 mL).The organic phase was dried (MgSO₄). Filtration and removal of thesolvent under reduced pressure gave(2R,6R,11R)-N-(2,4-dimethoxybenzyl)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide(360 mg, 86% yield); LC/MS (M+H)⁺=453.2.

(2R,6R,11R)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide

A mixture of(2R,6R,11R)-N-(2,4-dimethoxybenzyl)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide(360 mg, 0.80 mmol) in trifluoroacetic acid (5 mL) was stirred atambient temperature for 2 hours. The mixture was concentrated underreduced pressure before quenching with ice/ammonium hydroxide (28%) (25mL). The crude product was extracted twice using dichloromethane (100mL) and the combined organic layers dried (MgSO₄).

Filtration and removal of the solvent under reduced pressure gave thecrude product that was purified by prep-HPLC giving(2R,6R,11R)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide(130 mg, 54% yield); LC/MS (M+H)⁺=303.2.

(2R,6R,11R)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamidehydrochloride

To a solution of(2R,6R,11R)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzokflazocine-8-carboxamide(130 mg, 0.43 mmol) in ethyl acetate (10 mL) was added 2N HCl/ether (320μL, 0.64 mmol) and the mixture stirred for 1.5 hours. The solvent wasremoved under reduced pressure then freeze dried giving(2R,6R,11R)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamidehydrochloride (131 mg, 90% yield); LC/MS (M+H)⁺=303.22. ¹H-NMR (300 MHz,DMSO) δ 10.59-10.44 (br d, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.68 (d,1H), 7.31 (d, 1H), 7.20 (d, 1H), 3.84-3.49 (m, 3H), 3.49-2.95 (6H+H₂O),2.43-2.20 (m, 2H), 2.16-1.97 (m, 2H), 1.54-1.23 (m, 2H), 0.87-0.66 (m,3H).

A5. Experimental Procedure for Compound 1(4bS,9R)-4-hydroxy-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(A) and(4bR,9R)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-ol(B)

To a mixture of hydrocodone (2×22 g (2 batches), 147 mmol) and zincpowder (2×115 g, 3.46 mol) in acetic acid (2×1 L) was added conc. HCl(2×50 mL). The reaction was heated at 125° C. for 3 hours. Bothreactions were combined and filtered. The zinc wash washed withindustrial methylated spirits (1 L), and dichloromethane (1 L). Bothorganic washes and the acetic acid solution were concentrated underreduced pressure and the residue basified with ice/ammonium hydroxide(28%). The crude product was extracted into dichloromethane and dried(MgSO₄). Filtration and removal of the solvent under reduced pressuregave the crude products that were purified by silica chromatography (3%methanol/ammonia in dichloromethane) giving three batches of varyingpurity (2.4 g, (B); 20.5 g, 50% (A), 50% (B); 12.5 g, 65% (A), 10% (B));LC/MS (M+H)⁺=302.1 (A); LC/MS (M+H)⁺=288.2 (B).

(4bS,9R)-3-methoxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yltrifluoromethanesulfonate (C) and(4bR,9R)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yltrifluoromethanesulfonate (D)

To a solution containing a (1:1) mixture of(4bS,9R)-4-hydroxy-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(A) and(4bR,9R)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-ol(B) (20.5 g, 69 4 mmol) in tetrahydrofuran at 0° C. under an argonatmosphere was added sodium hydride (4.18 g, 60% in mineral oil, 104.5mmol). After 30 minutes N-Phenylbis(trifluoromethanesulfonamide) (37.3g, 104 4 mmol) was added and the mixture allowed to slowly return toambient temperature. The reaction was quenched with saturated aqueoussodium bicarbonate solution (500 mL) and extracted into ethyl acetate (1L). The organic phase was washed with brine and dried (MgSO₄).Filtration and removal of the solvent under reduced pressure gave thecrude product that was purified by silica chromatography (2.5%methanol/ammonia in dichloromethane) giving two batches of varyingpurity (11.0 g, (D); 15.1 g, 62% (C), 33% (D); LC/MS (M+H)⁺=434.1 (C);LC/MS (M+H)⁺=420.1 (D).

(4bR,9R)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene

A mixture of(4bR,9R)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yltrifluoromethanesulfonate(D) (11.0 g, 26.2 mmol), palladium acetate (590 mg, 2.63 mmol),1,3-bis(diphenylphosphino)propane (1.08 g, 2.61 mmol) and triethylsilane(10.0 mL, 62 6 mmol) in dimethylformamide (degassed) was heated at 60°C. overnight under an argon atmosphere. The reaction mixture was cooledto ambient temperature and partitioned between ethyl acetate (1 L) andwater (1 L). The organic phase was washed twice more with water (2×500mL). The combined aqueous phases were extracted using dichloromethane (2L total). The organic phase containing dichloromethane and dimethylformamide was concentrated under reduced pressure and the crude productpurified by silica chromatography (3% methanol/ammonia indichloromethane).

The same procedure was carried out with the 15.1 g batch (62% (C), 33%(D)). The material was purified as described above to give(4bR,9R)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene(8.6 g); LC/MS (M+H)⁺=272.0.

(4bR,9R)-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene

To a solution of(4bR,9R)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene(5.0 g, 18.44 mmol) in dichloromethane (400 mL) was added a solution ofCNBr (17 mL, 51 mmol, 3N in dichloromethane) under an argon atmosphere.The mixture was heated at reflux overnight. The solvent was removedunder reduced pressure and to the residue was added diethyleneglycol(100 mL) and KOH (16.6 g, 296 mmol). The reaction mixture was heated at160° C. for 2 hours, allowed to return to ambient temperature, thenpartitioned between dichloromethane (600 mL) and water (1 L). Theaqueous phase was washed twice more with dichloromethane and thecombined organic fractions dried (MgSO₄). Filtration and removal of thesolvent under reduced pressure gave the crude product that was purifiedby silica chromatography (10% methanol/ammonia in DCM) giving(4bR,9R)-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene(4.02 g, 85% yield); LC/MS (M+H)⁺=258.5.

(4bR,9R)-11-(1-cyclopropylethyl)-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene

A mixture of(4bR,9R)-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene(1.41 g), methylcyclopropyl ketone (17 mL, 172 mmol), and acetic acidwere heated at 70° C. for 1 hour. Sodium cyanoborohydride was added (830mg, 13.2 mmol) and the mixture heated at 70° C. overnight. The reactionmixture was portioned between ethyl acetate (500 mL) and saturatedsodium bicarbonate (500 mL). The organic phase was washed with brine anddried (MgSO₄). Filtration and removal of the solvent under reducedpressure gave the crude product that was purified by silicachromatography (2% methanol/ammonia in dichloromethane) giving(4bR,9R)-11-(1-cyclopropylethyl)-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene(0.75 g, 42% yield); LC/MS (M+H)⁺=326.1.

(4bR,9R)-11-(1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-ol

To an ice cooled solution of(4bR,9R)-11-(1-cyclopropylethyl)-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene(0.75 g, 2.31 mmol) in dichloromethane (50 mL) was added BBr₃ (0.9 mL,9.23 mmol) dropwise under an argon atmosphere. The reaction was stirredfor 3 hours then quenched with ammonia/methanol. The solvent was removedunder reduced pressure giving(4bR,9R)-11-(1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-ol (0.75 g, 100%yield); LC/MS (M+H)⁺=312.1.

(4bR,9R)-11-(1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-yltrifluoromethanesulfonate

To a solution of(4bR,9R)-11-(1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-ol(0.75 g, 2.41 mmol) and triethylamine (1.0 mL, 7.23 mmol) indichloromethane (50 mL) was addedN-Phenylbis(trifluoromethanesulfonamide) (0.95 g, 2.65 mmol) and themixture stirred at room temperature overnight. The solvent wasconcentrated under reduced pressure and the residue partitioned between20% hexane in ethyl acetate (300 mL) and water (150 mL). The organiclayer was washed four more times more with water and dried (MgSO₄).Filtration and removal of the solvent under reduced pressure gave(4bR,9R)-11-(1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-yltrifluoromethanesulfonate (0.78 g, 73% yield); LC/MS (M+H)⁺=444.1.

(4bR,9R)-11-(1-cyclopropylethyl)-N-(2,4-dimethoxybenzyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide

To a solution of(4bR,9R)-11-(1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-yltrifluoromethanesulfonate(0.78 g, 1.76 mmol) in degassed dimethyl sulfoxide (15 mL), was addedN-hydroxysuccinimide (405 mg, 3.52 mmol), palladium acetate (79 mg,0.352 mmol), triethylamine (490 μL, 3.52 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (203 mg, 0.352 mmol).The reaction mixture was heated with carbon monoxide (latm) at 75° C.overnight. The reaction mixture was cooled to ambient temperature and2,4-dimethoxybenzylamine (294 mg, 1.76 mmol) added. The mixture wasstirred for 1 hour before partitioning between water (300 mL) and ethylacetate (400 mL). The aqueous phase was extracted twice more with ethylacetate. The combined organic phase was dried (MgSO₄), filtered, and thesolvent removed under reduced pressure. The crude material was purifiedby silica chromatography (3% methanol in dichloromethane) to give(4bR,9R)-11-(1-cyclopropylethyl)-N-(2,4-dimethoxybenzyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(1.0 g, contains impurities—used directly in next step); LC/MS(M+H)⁺=489.1.

(4bR,9R)-11-((R)-1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide

A mixture of(4bR,9R)-11-(1-cyclopropylethyl)-N-(2,4-dimethoxybenzyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(1.0 g, 2.05 mmol) in trifluoroacetic acid (30 mL) was stirred at roomtemperature for 2 hours. The mixture was concentrated under reducedpressure before quenching with ice/ammonium hydroxide (28%) (50 mL). Thecrude product was extracted twice using dichloromethane (200 mL) and thecombined organic layers dried (MgSO₄). Filtration and removal of thesolvent under reduced pressure gave the crude product that was purifiedand separated from the (S)-diastereomer using prep-HPLC giving(4bR,9R)-11-(R)-1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(64 mg, 10% yield); LC/MS (M+H)⁺=339.3.

(4bR,9R)-11-((R)-1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride

To a solution of(4bR,9R)-11-((R)-1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(64 mg, 0.19 mmol) in ethyl acetate (15 mL) was added 2N HCl/ether (140μL, 0.28 mmol) and the mixture stirred for 30 minutes. The solvent wasremoved under reduced pressure then freeze dried giving(4bR,9R)-11-((R)-1-cyclopropylethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride (71 mg, 100% yield); LC/MS (M+H)⁺=339.3. ¹H-NMR (400 MHz,DMSO) δ 10.41 (br s, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.68 (d, 1H), 7.30(s, 1H), 7.22 (d, 1H), 4.18 (s, 1H), 3.57-3.03 (m, 3H+H₂O), 2.95 (d,1H), 2.55 (d, 1H), 2.37-2.16 (m, 2H), 2.08-1.87 (m, 1H), 2.68-0.51 (m,15H), 0.20 (s, 1H).

A6. Experimental Procedure for Compound E and a Hydrochloride SaltThereof

Synthesis of(4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile

To a solution of cyclobutane carboxaldehyde (19.45 g, 231 2 mmol) indichloromethane (500 mL) was added(4R,4aR,7aR,12bS)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile(25 g, 77.1 mmol). The reaction was stirred for 60 minutes at roomtemperature before sodium triacetoxyborohydride (32.7 g, 154.0 mmol) wasadded portionwise over 20 minutes. After one hour, the reaction wasquenched with NaHCO₃ solution and extracted with dichloromethane (×3).The dichloromethane phases were combined, washed with brine, dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby silica chromatography eluted with dichloromethane to 7% methanol indichloromethane to give(4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile(31.1 g, 98% pure LCMS, assume quant.); [M+H]⁺393.1.

Synthesis of(4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carbonitrile

A suspension of(4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile(31.1 g, 79.2 mmol) in 6M HCl (aq) (250 mL) was stirred at roomtemperature at room temperature for 24 hours. Further 6M HCl was added(25 mL) and stirred for an additional 24 hours. The reaction was pouredonto ice/NH_(3(aq)) and stirred for 30 minutes and the solid collectedby suction filtration and washed with water. The solid was dissolved indichloromethane and washed with brine, dried over MgSO₄ and concentratedunder reduced pressure to give(4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carbonitrile(26.1 g, 96% pure LCMS, 95% yield); [M+H]⁺367.2.

Synthesis of(4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide

To a solution of(4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carbonitrile(24 g, 68.9 mmol) in tert-butanol (240 mL) was added KOH (2.1 g, 37.1mmol). The reaction was heated to 100° C. for 15 minutes. The reactionwas allowed to cool to room temperature and concentrated to 50% volume.Diluted with water and extracted with ethyl acetate twice. The organicphases were combined, washed with sodium hydrogen carbonate solution andbrine and dried over MgSO₄ and concentrated under reduced pressure. Theresidue was purified by silica chromatography eluted with 4% methanol indichloromethane to give to give(4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide(14.2 g, 89% pure LCMS, 56% yield); [M+H]⁺367.2.

Synthesis of(4bS,8aR,9R)-11-(cyclobutylmethyl)-4-hydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(Compound E)

To a solution of(4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide(14.2 g, 38.75 mmol) in ethanol (500 mL) was added ammonium chloride(31.1 g, 581 mmol) followed by zinc powder (25.3 g, 388 mmol). Thereaction was heated to reflux for 2.5 hours. The reaction was cooled to˜50° C. and filtered through a pad of celite. The celite was washed withethanol/methanol. The filtrate was concentrated under reduced pressure.The residue was partitioned between dichloromethane and NH_(3(aq))/H₂O(1:1) and the aqueous phase re-extracted with dichloromethane. Thecombined dichloromethane phase was washed with brine, dried over MgSO₄and concentrated. The crude product was purified by silicachromatography and eluted with 3.5% NH₃/methanol in dichloromethane togive(4bS,8aR,9R)-11-(cyclobutylmethyl)-4-hydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(9.7 g, 98.5% pure LCMS, 68% yield); [M+H]⁺369.2.

Synthesis of(4bS,6S,8aR,9R)-11-(cyclobutylmethyl)-4,6-dihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride

1M K-selectride in tetrahydrofuran (49.9 mL) was added to a solution of(4bS,8aR,9R)-11-(cyclobutylmethyl)-4-hydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(9.2 g, 25.0 mmol) in tetrahydrofuran (150 mL) cooled in an ice bath.After 30 minutes a saturated solution of ammonium chloride was added andthe reaction mixture extracted with ethyl acetate (×3). The combinedorganic phase was washed with sodium hydrogen carbonate solution andbrine, dried over MgSO₄ and concentrated. The residue was taken up in 2MHCl aq and washed with ethyl acetate. The aqueous phase was basifiedwith 2 M NaOH to pH 7 then sodium hydrogen carbonate solution was added.The aqueous solution was extracted with dichloromethane (×3) dried overMgSO₄, concentrated, and purified via prep HPLC (30-50% acetonitrile in0.1% NH₄HCO₃ pH10 buffer) to give(4bS,8aR,9R)-11-(cyclobutylmethyl)-4-hydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(4.7 g, 99.76% pure LCMS, 51% yield); [M+H]⁺371.19.

To a solution of(4bS,8aR,9R)-11-(cyclobutylmethyl)-4-hydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(4.6 g, 12 4 mmol) in ethyl acetate (30 mL) and dichloromethane (30 mL)was added 2M HCl in diethyl ether (7.45 mL, 14.9 mmol). After 2 hours,the liquors were removed under reduced pressure and the residuesuspended in diethyl ether, collected by suction filtration and washedwith diethyl ether. The solid was dissolved in 9:1 water/methanol andfreeze dried togive(4bS,6S,8aR,9R)-11-(cyclobutylmethyl)-4,6-dihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride (4.7 g, 99.81% pure LCMS, 93% yield); [M+H]⁺371.19. ¹H NMR(300 MHz, D₂O) 7.37 (1H, d), 6.62 (1H, d), 3.99 (1H, br s), 3.66 (1H, brd), 3.51 (1H, br s), 2.91-3.27 (5H, m), 2.44-2.62 (2H, m), 1.23-2.05(14H, m).

A7. Experimental Procedure for Compound B and a Hydrochloride SaltThereof

Synthesis of (4bS,8aR,9R)-11-(cyclopropylmethyl)-5 ,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile

To a solution of(4bS,8aR,9R)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile(3.58 g, 11.5 mmol) in dichloromethane (115 mL) was addedcyclopropylcarboxaldehyde (2.55 mL, 34.6 mmol). The reaction was stirredfor 60 minutes at room temperature before sodium triacetoxyborohydride(4.90 g, 23.1 mmol) was added portionwise. After one hour, the reactionwas quenched with aqueous NaHCO₃ solution and extracted withdichloromethane (×3). The dichloromethane phases were combined, washedwith brine, dried over MgSO₄ and concentrated under reduced pressure.The residue was purified by silica chromatography eluted withdichloromethane to 5% methanol in dichloromethane to give(4bS,8aR,9R)-11-(cyclopropylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile(3.59 g, 98.5% pure LCMS, 86% yield); [M+H]⁺365.2.

Synthesis of (4bS,8aR,9R)-11-(cyclopropylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carboxamide

To a solution of(4bS,8aR,9R)-11-(cyclopropylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile(3.95 g, 9 9 mmol) in dimethylsulfoxide (40 mL) was added potassiumcarbonate (4.09 g, 29.6 mmol). The reaction was cooled to 15° C. andhydrogen peroxide (12 mL, 35% aqueous solution) added dropwisemaintaining the temperature between 15 and 20° C. After addition wascomplete, the reaction was allowed to warm to room temperature. Thereaction was cooled to 0° C., quenched with water and extracted withethyl acetate. The reaction was basified with sodium hydrogen carbonatesolution to pH 10 and extracted with ethyl acetate (×3). The organicswere combined, washed with water (×3), brine, dried over MgSO₄ andconcentrated under reduced pressure. The product was purified by silicachromatography eluted with a gradient from 100% dichloromethane to 10%NH₃/methanol in dichloromethane to give(4bS,8aR,9R)-11-(cyclopropylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carboxamide(2.76 g, 98.3% pure LCMS, 73% yield); [M+H]⁺383.2.

Synthesis of(4bS,8aR,9R)-11-(cyclopropylmethyl)-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride

To(4bS,8aR,9R)-11-(cyclopropylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carboxamide(2.76 g, 7 2 mmol) was added 6M HCl (aq) (60 mL) with cooling. After anhour the reaction was poured onto ice/NH_(3(aq)) and extracted withdichloromethane (×3). The dichloromethane phases were combined, washedwith brine, dried over MgSO₄ and concentrated under reduced pressure.The residue was purified by silica chromatography eluted with 100%dichloromethane to 10% NH₃/methanol in dichloromethane to give CompoundB:(4bS,8aR,9R)-11-(cyclopropylmethyl)-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(2.41 g, 97.5% pure LCMS, 96% yield).

To(4bS,8aR,9R)-11-(cyclopropylmethyl)-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(2.39 g, 7 1 mmol) in ethyl acetate (60 mL) was added 2M HCl in diethylether (3.87 mL, 7.8 mmol). The product precipitated from solution andwas collected by filtration. The solid was washed with ethyl acetate anddiethyl ether before drying under vacuum. The product was dissolved inwater and freeze dried to give(4bS,8aR,9R)-11-(cyclopropylmethyl)-6-oxo-6,7,8,8 a,9,10-hexahydro -5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide hydrochloride (2.62 g,99.9% LCMS, 99% yield); M+H⁺339.3. ¹H NMR (300 MHz, D₂O) 7.60 (1H, s),7.43 (1H, d), 7.17 (1H, d), 4.07 (0.8H, d), 3.97 (0.2H, d), 2.34-3.44(10H, m), 1.74-2.18 (3H, m), 1.60 (0.8H, d), 1.44 (0.2H, d), 1.27 (1H,dq), 0.96 (1H, m), 0.59 (2H, d), 0.25 (2H, m).

A8. Experimental Procedure for: Synthesis of(4bS,8aR,9R)-11-(cyclobutylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile

To a solution of cyclobutylmethanol (3.70 g, 42.9 mmol) indichloromethane (100 mL) was added silica (25 g), followed by pyridiniumchlorochromate (18.52 g, 85.9 mmol). The reaction mixture was stirredfor 2 h and filtered through a plug of silica eluting withdichloromethane (300 mL). The resulting solution was concentrated toabout 75 mL and(4bS,8aR,9R)-5,7,8,8a,9,10-hexahydrospirol9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolanel-3-carbonitrile(0.40 g, 0.13 mmol) added, followed by sodium triacetoxyborohydride(0.71 g, 0.34 mmol). The reaction mixture was stirred for 2 h, washedwith aqueous sat. NaHCO₃ (100 mL) and dried over MgSO₄. After filtrationand evaporation the residue was further purified by silica columnchromatography eluting with 5-10% methanol/dichloromethane to give thedesired product(4bS,8aR,9R)-11-(cyclobutylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile as a yellow oil (0.48 g, 56% pure LCMS);[M+H]⁺379.3. This was used in the next reaction without furtherpurification.

Synthesis of(4bS,8aR,9R)-11-(cyclobutylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carboxamide

To(4bS,8aR,9R)-11-(cyclobutylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carbonitrile (0.48 g, 13 mmol) in dimethylsulfoxide (12 mL)was added potassium carbonate (0.53 g, 3.8 mmol). The reaction wascooled to 15° C. and hydrogen peroxide (2.0 mL, 35% aqueous solution)added dropwise maintaining the temperature between 15 and 20° C. Afteraddition was complete, the reaction was allowed to warm to roomtemperature. The reaction was cooled to 0° C., quenched with water andextracted with ethyl acetate. The reaction was basified with sodiumhydrogen carbonate solution and extracted with ethyl acetate (×3). Theorganics were combined, washed with water (×3), brine, dried over MgSO₄and concentrated under reduced pressure. The product was purified bysilica chromatography eluted with a gradient from 10% methanol indichloromethane to 5% NH₃/methanol in dichloromethane to give(4bS,8aR,9R)-11-(cyclobutylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carboxamide (0.27 g, 94% pure LCMS, 54% yield over twosteps); [M+H]⁺397.3.

Synthesis of(4bS,8aR,9R)-11-(cyclobutylmethyl)-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride

To(4bS,8aR,9R)-11-(cyclobutylmethyl)-5,7,8,8a,9,10-hexahydrospiro[9,4b-(epiminoethano)phenanthrene-6,2′-[1,3]dioxolane]-3-carboxamide(274 mg, 0.69 mmol) was added 6M HCl (aq) (12 mL). The reaction wasstirred for 24 hours until complete. The reaction was poured ontoice/NH_(3(aq)) and extracted with dichloromethane (×3). Thedichloromethane phases were combined, washed with brine, dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby silica chromatography eluted with 5-10% NH₃/methanol indichloromethane to give(4bS,8aR,9R)-11-(cyclobutylmethyl)-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(225 mg, 99.2% pure LCMS, 93% yield).

To(4bS,8aR,9R)-11-(cyclobutylmethyl)-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(225 mg, 0.64 mmol) in ethyl acetate (10 mL) was added 2M HCl in diethylether (0.35 mL, 0.70 mmol). The product precipitated from solution andthe liquors were concentrated under vacuum. The solid was trituratedwith diethyl ether before drying under vacuum. The product was dissolvedin water and freeze dried to give(4bS,8aR,9R)-11-(cyclobutylmethyl)-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride (237 mg, 99.3% LCMS, 89% yield); [M+H]⁺353.2. ¹H NMR (300MHz, D₂O) 7.69 (1H, s), 7.59 (1H, dd), 7.29 (1H, d), 3.84 (1H, s),2.48-3.55 (11H, m), 1.31-2.31 (11H, m).

A9. Experimental Procedure for: Synthesis of(4bS,6S,8aR,9R)-11-(cyclobutylmethyl)-6-hydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride

To a solution of(4bS,8aR,9R)-11-(cyclobutylmethyl)-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(84 mg, 0.24 mmol) in methanol (4 mL) was added sodium borohydride (18mg, 0.48 mmol) at room temperature. The reaction was stirred for an hourbefore quenching with ammonium chloride solution. The aqueous phase wasbasified with 2M NaOH solution and extracted with dichloromethane (×4).The dichloromethane phases were combined, washed with brine, dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby silica chromatography eluted with 10% NH₃/methanol in dichloromethaneto separate the diastereoisomers. The major diastereoisomer was thedesired(4bS,6S,8aR,9R)-11-(cyclobutylmethyl)-6-hydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(50 mg, 98.1% pure LCMS, 59% yield).

To(4bS,6S,8aR,9R)-11-(cyclobutylmethyl)-6-hydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamide(50 mg, 0.14 mmol) in ethyl acetate (4 mL) was added 2M HCl in diethylether (0.07 mL, 0.70 mmol). The solvent was removed under vacuum beforefreeze drying from water to give(4bS,6S,8aR,9R)-11-(cyclobutylmethyl)-6-hydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamidehydrochloride (55 mg, 99.0% pure LCMS, 100% yield); [M+H]⁺355.3. ¹H NMR(300 MHz, D₂O) 7.76 (1H, s), 7.44 (1H, d), 7.16 (1H, d), 4.02 (1H, s),3.58 (1H, s), 2.88-3.44 (5H, m), 2.70 (1H, d), 2.55 (1H, m), 2.35 (1H,dt), 0.99-2.16 (14H, m).

Par B. Biological Assay B1. In Vitro Characterization

The in vitro kinetic and pharmacological characteristics of thecompounds set forth in Table B, Table C, Table D, and Table E are testedusing the following assays.

Opioid Receptor Binding assay

The K_(i) (binding affinity) for μ opioid receptors was determined usinga competitive displacement assay as previously described in Neumeyer(Journal of Med. Chem. 2012, p 3878), which is incorporated herein inits entirety. Briefly, membrane protein from CHO (Chinese HamsterOvarian) cells that stably expressed the cloned human μ opioid receptorwere incubated with 12 different concentrations of the compound setforth herein in the presence of 0.25 nM [3H]DAMGO (see Tiberi et al.,Can. J. Physiol. Pharmacol. 1988, Vol. 66, p 1368, which is incorporatedby reference herein in its entirety) in a final volume of 1 mL of 50 mMTris-HCl, pH 7.5 at 25° C. Incubation times of 60 min were used for[3H]DAMGO (see Gulati et al., Life Sci. 1990, Vol. 47, p 159, which isincorporated by reference herein in its entirety). Nonspecific bindingwas measured by inclusion of 10 μM naloxone. The binding was terminatedby filtering the samples through Schleicher & Schuell No. 32 glass fiberfilters using a Brandel 48-well cell harvester. The filters weresubsequently washed three times with 3 mL of cold 50 mM Tris-HCl, pH7.5, and were counted in 2 mL Ecoscint A scintillation fluid. IC50values were calculated by least squares fit to a logarithm-probitanalysis. Ki values of unlabelled compounds were calculated from theequation Ki=(IC50)/1+S where S=(concentration of radioligand)/(Kd ofradioligand) (Cheng and Prusoff, 1973). The calculated IC50 and Kivalues for the compounds tested are set forth in Table B, Table C, TableD, and Table E, herein.

Functional Assay (GTPγS Binding)

The EC50 and Imax for μ opioid receptors was determined using a[I³⁵S]GTPγS binding assay. This assay measures the functional propertiesof a compound by quantifying the level of G-protein activation followingagonist binding in studies using stably transfected cells, and isconsidered to be a measure of the efficacy of a compound. Membranes fromCHO (Chinese Hamster Ovary) cells that stably expressed the cloned humanMu opioid receptor were used in the experiments. Specifically, in afinal volume of 0.5 mL, 12 different concentrations of each testcompound were incubated with 7.5 μg of CHO cell membranes that stablyexpressed the human μ opioid receptor. The assay buffer consisted of 50mM Tris-HCl, pH 7.4, 3 mM MgCl2, 0.2 mM EGTA, 3 μM GDP, and 100 mM NaCl.The final concentration of [35S]GTPγS was 0.080 nM. Nonspecific bindingwas measured by inclusion of 10 μM GTPγS. Binding was initiated by theaddition of the membranes. After an incubation of 60 min at 30° C., thesamples were filtered through Schleicher & Schuell No. 32 glass fiberfilters. The filters were washed three times with cold 50 mM Tris-HCl,pH 7.5, and were counted in 2 mL of Ecoscint scintillation fluid. Dataare the mean Emax and EC50 values±S.E.M. For calculation of the Emaxvalues, the basal [35S]GTPγS binding was set at 0%, and the 100%[35S]GTPγS binding level was set at the maximum binding achieved withDAMGO. To determine antagonist activity of a compound at the μ opioidreceptors, CHO membranes expressing the μ opioid receptor, wereincubated with 12 different concentrations of the compound in thepresence of 200 nM of the μ agonist DAMGO. The Emax values are themaximal percentage increase of [35S]GTPγS binding induced by a testcompound relative to basal [35S]GTPγS binding in the absence of anydrug. Data for antagonists are the mean Imax and IC50 values±S.E.M. Thecalculated EC50 and Imax values for the compounds tested are set forthin Table B, Table C, Table D, and Table E, herein. It should be notedthat the GTPγS binding assay described above is performed underconditions such that the observed Emax value for buprenorphine in thisassay is at least 50% compared to baseline.

TABLE D μ Ki/ μ EC50/ μ Emax/ μ IC50/ μ Imax/ Compound nM nM % nM %

0.083 1.3 18 1.7 82

0.14 — 11 0.65 86

5.8 7.7 43 91

1.2 — 11 38 86

0.12 2.2 46 14 41

0.098 2.5 54 7.8 59

0.1 0.89 21 1.5 80

0.05 20 58 89 morphine 0.32 34 ± 14 96.5 ± 36  No No inhibitioninhibition nalbuphine 1.3 ± 0.4 21 ± 15   26 ± 1.55 88 ± 18 74 ± 2 buprenorphine 0.41  0.30 ± 0.042  53 ± 2.3  0.45 ± 0.060  48 ± 1.7

B2. Thermal Pain Assay

The antinociceptive effect of the compounds disclosed herein isdetermined using a rodent hot plate model. This model tests theresponses to acute thermal pain in rats as set forth below.

Male Sprague-Dawley rats (275-425g) are used for all studies. Rats arehoused 2/cage and are given food and water ad libitum. Body weights weretaken once before testing begins and rats were marked on their tail toindicate numbering. The hot plate apparatus (Columbus Instruments) wasused to measure antinociception to acute thermal pain.

Rats are placed individually on the hot plate apparatus (surfacetemperature is equal to 52.5° C. and is confirmed with an infraredthermometer at the beginning of each study) and the response latency tolick either hind paw is recorded. The maximum response latency (MRL) isset to 60 seconds to avoid potential thermal injury associated withlonger exposure times. Rats are tested for a baseline hot plate response(licking one hind paw) immediately prior to subcutaneous injection withtest compound. Any rat which displays a baseline response latencygreater than 30 seconds is removed from the study. The latency to lick ahind paw is compared to the dose of morphine (7.5 mg/kg, SC) thatproduced a maximum response latency of 60 seconds when measured 30minutes after administration. Following test compound administration,rats are tested 30, 60, 90, 120, and 240 minutes later on the hot plate.The time to lick one hind paw is recorded as the response latency foreach rat.

Raw data is reported as the time (in seconds) to lick one hind pawfollowing exposure to the hot plate. The mean and SEM of the responseslatencies for each experimental group are calculated and a line graphdepicting mean hot plate latency vs. time is generated using GraphPadPrism. An increase in mean response latency above baseline followingtest compound administration is indicative of an antinociceptive effect.

In one study, the antinociceptive effects of Compound A, either alone orin combination with morphine were determined using the hot plate assaydescribed above. Specifically, rats were administered: 1) 5 mg/kgmorphine; 2) 1 mg/kg Compound A; 3) 5 mg/kg morphine and 0.01 mg/kgCompound A; 4) 5 mg/kg morphine and 0.1 mg/kg Compound A; or 5) 5 mg/kgmorphine and 1 mg/kg Compound A. The results, set forth in FIG. 1, showthat although Compound A inhibits morphine analgesia at doses rangingfrom 0.01 mg/kg to 1 mg/kg, Compound A alone has no antinociceptiveeffect at a dose of 1 mg/kg.

In another study, the antinociceptive effects of Compound A andbuprenorphine were compared using the hot plate assay described above.Specifically, rats were administered with either 10 mg/kg of Compound A,or 1 mg/kg of buprenorphine. The results, set forth in FIG. 2, show thatbuprenorphine inhibits thermal pain in rats at a dose of 1 mg/kg,whereas Compound A has no antinociceptive effect at a dose of 10 mg/kg.

In another study, the antinociceptive effects of morphine, and CompoundsB, C, D, and E, separately, were determined using the hot plate assaydescribed above.

Specifically, rats were administered: 1) 7.5 mg/kg morphine; 2) 10.0mg/kg Compound B; 3) 10.0 mg/kg Compound C; 4) 10.0 mg/kg Compound D; or5) 10.0 mg/kg Compound E. The results, set forth in FIG. 4, show thatmorphine inhibits thermal pain at a dose of 7.5 mg/kg, and thatCompounds B, C, D, or E have no antinociceptive effect at a dose of 10.0mg/kg.

B3. In vivo Dopamine Efflux Assay

The neurochemical response of the compounds disclosed herein isdetermined by in vivo microdialysis in awake rats. Intra-cranialmicrodialysis in rats allows the sampling of extracellular cerebrospinalfluid (CSF) from specific brain regions of interest and the measurementand quantitation of neurotransmitter, neuropeptide, and drugconcentrations following the analysis of sampled dialysate withbioanalytical chemistry techniques. This technique allows measurementand comparison of neurotransmitter release in response to test compoundsto basal neurotransmitter levels. The nucleus accumbens shell is a brainregion which is critically important for understanding the rewardingeffects of a variety of stimuli including food, mating behavior anddrugs of abuse. Rewarding stimuli have been shown to act though multiplepathways to modulate the mesolimbic dopamine system, ultimatelyresulting in acute increases in extracellular DA (DA_(ext)) within thenucleus accumbens shell following systemic administration orself-administration. In these studies, microdialysate collected fromprobes implanted in the NAc-sh is analyzed for dopamine content by HPLCcoupled to electrochemical detection (HPLC-EC) as set forth below.

Male Wistar rats (275-425g) are used for all studies. Rats were housed2/cage and are given food and water ad libitum. Approximately 3-4 daysafter arrival to the animal facility, rats underwent surgicalimplantation of microdialysis guide cannula to guide insertion of themicrodialysis probe. Rats are anesthetized with a mixture ofketamine/xylazine (80/6 mg/kg IP) and placed in a stereotaxic apparatus.Ophthalmic lubricating petroleum based ointment is applied to the eyesas needed. The surgical area is shaved and prepared with a betadinescrub and wiped with alcohol. The skull is exposed and small burr holeswere drilled to allow for the guide cannula to pass through and for themounting screws to be attached to the skull. Guide cannula (CMA-12,CMA-Microdialysis, SWE) are stereotaxically implanted towards the NAc-sh(final microdialysis coordinates relative to bregma: A/P+1.70; M/L±0.80;D/V -5.90 from the top of the skull) (Paxinos and Watson, “The RatBrain”, 6th Edition, 2008). Each guide cannula is secured with 3, ⅛″skull screws (Small Parts Inc, USA) and cranioplastic cement (GC FujiPlus Capsule; Henry Schein, USA). Following 3-4 days of recovery,microdialysis probes (CMA-12, CMA-Microdialysis, SWE) with a 2 mm activemembrane length are inserted through the guide cannula and rats areindividually tethered to a CMA 120 microdialysis system(CMA-Microdialysis, SWE). Rats are continuously perfused overnight withsterile artificial cerebrospinal fluid (aCSF) (CMA CNS PerfusionSolution; CMA-Microdialysis, SWE) via a syringe pump at 0.2 μl/minute.The following morning, continuous perfusion of aCSF was increased to 2.0μl/minute and the flow rate was equilibrated for at least 2 hours priorto experimentation.

Microdialysis occurred on the day following probe insertion.Microdialysis samples are collected automatically at 15 minute intervalsvia a chilled microfraction collector for a total of 6.0 hours.Following equilibration, a 1.5 hour baseline measurement (6 fractions)of neurotransmitter levels is collected. Following baselinemeasurements, rats are separately administered various concentrations oftest compound. Fractions were analyzed via HPLC-EC to determine dopamineconcentrations.

Microdialysis fractions are analyzed via HPLC-EC using an AlexysMonoamine Analyzer (Antec Leyden, NLD) or via UHPLC-EC using an AlexysNeurotransmitter Analyzer. For HPLC-EC detection, an aliquot of eachfraction (10 ul) is injected onto a 1 μm reverse-phase C18 column(HSS-T3, Waters Corp., Milford, Mass.). DA is eluted using a mobilephase (pH 6.0) consisting of 50 mM phosphoric acid, 8 mM KCL, 0.1 mMEDTA, 6.5% acetonitrile, and 1200 mg/L octane sulfonic acid. DA isdetected using a Decade II amperometric detector (Antec Leyden) with aglassy carbon electrode maintained at approximately 0.460V relative to asalt-bridge reference electrode. For UHPLC-EC detection, an aliquot ofeach fraction (10 ul) is injected onto a 1 μm reverse-phase C18 column(HSS T3, Waters Corp., Milford, Mass.). DA is eluted using a mobilephase (pH 4.00) consisting of 50 mM phosphoric acid, 8 mM KCL, 50 mMCitric Acid, 0.1 mM EDTA, 6.5% acetonitrile, and 600 mg/L octanesulfonic acid. DA is detected using a Decade II amperometric detector(Antec Leyden) with a glassy carbon electrode maintained atapproximately 0.55V relative to a Ag/AgCl reference electrode.

All data is recorded and analyte levels quantitated using a Clarity 3.0software package (Data Apex, Czech Republic). A 6-point standard curve(0.25, 0.5, 1.0, 2.0, 4.0 and 8.0 pg DA/10 μl injection) is run dailyprior to neurotransmitter analysis. The standard curve is fittedlinearly and neurotransmitter content in microdialysate samples isquantitated based on the corresponding standard curve. The amount ofdopamine or metabolites is quantified as “on-column” in picograms ofanalyte per 10 μl sample injection onto the column Raw data are reportedas picograms of dopamine per 10 μl sample and transformed (using GraphPad Prism 5.0) to percentage of pre-drug baseline for each animal, asdefined as the average of the six baseline microdialysis samples.Percentage change from baseline vs. time is then graphed using GraphPadPrism 5.0. Following completion of the study, all animals are analyzedvia histological methods to ensure proper probe placement with thenucleus accumbens shell. Those animals with probe placement outside ofthe nucleus accumbens shell are excluded from the final data analysis

To verify probe placement, rats are euthanized with an IP injection of50% Euthasol (Virbac, AH Inc, Forth Worth, Tex.) shortly aftermicrodialysis. Brains are rapidly dissected and frozen on dry ice andstored at -80° C. Coronal sections (approximately 60-um) are then slicedat the level of the nucleus accumbens and digitally photographed forarchival purposes. Only data from animals with verified probe placementare included in data analysis.

In one study, the amount of dopamine release induced by Compound A andbuprenorphine in the rat nucleus accumbens was determined using themicrodialysis assay herein. Specifically, rats were separatelyadministered with Compound A (at 0.01 mg/kg, 0.1 mg/kg, or 1 mg/kg) orbuprenorphine (at 0.001 mg/kg, 0.003 mg/kg, 0.01 mg/kg, 0.1 mg/kg, or 1mg/kg) and microdialysate was sampled for 4.5 hours (18 fractions). Theresults of these experiments are set forth in FIG. 3. These data showthat Compound A induced a dose dependent increase in dopamine efflux inthe rat nucleus accumbens, achieving a maximum dopamine efflux of about300% over baseline at 0.1 mg/kg of Compound A. Buprenorphine alsoinduced a dose dependent increase in dopamine efflux. Although, nomaximum dopamine efflux level for buprenorphine was determined, themaximum dopamine efflux induced by buprenorphine is clearly much greaterthan that obtainable using Compound A. The lower ceiling level ofdopamine efflux of exhibited by Compound A relative to buprenorphineindicates that Compound A will likely have a lower risk of opioiddependence, opioid addiction and/or opioid withdrawal symptoms comparedto buprenorphine.

In other studies, the amount of dopamine release induced by Compounds B,C, D, and E in the rat nucleus accumbens was determined using themicrodialysis assay herein. Specifically, rats were administered (viasubcutaneous injection at T=0) separately with Compounds B, C, D, or Eat doses of 0.1 mg/kg, 1 mg/kg, or 10 mg/kg, and microdialysate wascontinuously sampled for 4.5 hours. The results of these experiments areset forth in FIGS. 5-8. Compound B exhibited a maximum dopamine effluxof about 150% to about 200% over baseline at a dose of 10 mg/kg.Compound C exhibited a maximum dopamine efflux of about 125% to about200% over baseline at the three dose levels. Compounds D and E exhibiteda maximum dopamine efflux of about 125% to about 250% over baseline atthe three dose levels. These low ceiling levels of dopamine effluxindicate that Compounds B, C, D, and E will likely have a lower risk ofopioid dependence, opioid addiction and/or opioid withdrawal symptoms.

B4. In vivo Forced Swim Test

The Forced Swim Test is a classical preclinical model used to assessantidepressant effects of test compounds in rats. Rats forced to swim inan inescapable cylinder adopt a characteristic immobile posture after aperiod of vigorous swimming Immobility has been shown to be reduced bymost clinically effective antidepressant drugs. Furthermore, thisparadigm has the benefit of being able to distinguish potentialantidepressant compounds from other behavioral paradigms that measureactivities (open-field) or other compounds that might havedose-dependent effects on general locomotor activities unrelated tomood.

A male, Wistar-Kyoto rat is placed into its assigned clear Plexiglascylinders of water (23-25° C.) for a 15-min pretest swim. A compound isthen administered in the rat by subcutaneously (sub-Q) injectionsfollowing a dosing schedule. The sub-Q dosing schedule includes oneinjection at 0.5 hr after the pretest swim, one injection at 5 hrsbefore a test swim, and one injection at lhr before the test swim. Eachtest swim lasts 6 minutes, and this test swim is carried out within 24hours after the pretest swim. The test swim is recorded using a digitalvideo recording system and subsequently analyzed manually for immobilitybehavior.

In one study, reductions of the duration of immobility in rats inducedby different doses of Compounds A, B and C were determined using theForced Swim Test herein. Specifically, rats were administered with avehicle (saline), Compound A, Compound B, or Compound C at a dose rangebetween 0 and 10 mg/kg, and durations of immobility were recorded. Theresults of these experiments are set forth in FIG. 9. Maximal effects ofCompounds A, B and C in the Forced Swim Test are shown in FIGS. 9( a),9(b) and 9(c), respectively. Compounds A, B and C significantly (p<0.05)decreased immobility time in the Forced Swim Test compared to salinetreated controls. The reductions of immobility indicate that CompoundsA, B and C will likely improve depressive-like behavior.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the following claims.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications andother references cited herein are hereby expressly incorporated hereinin their entireties by reference.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R₁ is cyclobutylor

R₂ is H or methoxy; and R₃ and R₄ are each, independently, H, hydroxyl,or NR₅R₆ wherein R₅ and R₆ are each independently H, alkyl, orsubstituted acyl, or alternatively, R₃ and R₄, together with the carbonatom to which they are attached, form C═O or C═CH₂.
 2. (canceled) 3.(canceled)
 4. (canceled)
 5. A compound selected from

or a pharmaceutically acceptable salt thereof.
 6. A compound of FormulaII:

or a pharmaceutically acceptable salt thereof, wherein R₁ is C₁-C₆alkyl, C₂-C₆ alkenyl, cycloalkyl, heterocyclyl, hydroxyalkyl, oralkoxyalkyl; R₂ and R₃ are each C₁-C₄ alkyl, or alternatively, R₂ andR₃, together with the carbon atoms to which they are attached, form a6-membered carbocyclic ring which is optionally substituted with aketone, a hydroxyl, or a NR₅R₆ group wherein R₅ and R₆ are eachindependently H, alkyl, or substituted acyl group; when

is a single bond, R₄ is H; and when

is a double bond, R₄ is O.
 7. (canceled)
 8. (canceled)
 9. (canceled) 10.A compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein R₁ is C₁-C₆alkyl, C₂-C₆ alkenyl, cycloalkyl, heterocyclyl, hydroxyalkyl, oralkoxyalkyl; R₂ and R₃ are each H or C₁-C₄ alkyl, or alternatively, R₂and R₃, together with the carbon atoms to which they are attached, forma 6-membered unsubstituted carbocyclic ring, or a 6-membered carbocyclicring optionally substituted with a hydroxyl, a ketone, or a _(NR50R60)group, wherein R₅₀ and R₆₀ are each independently H, alkyl, orsubstituted acyl; R₄ and R₅ are each, independently, H, hydroxyl, ortaken together with the carbon atom to which they are attach to, form aC═O group; R₆ is unsubstituted or substituted C₆-C₁₀ aryl, orsubstituted or unsubstituted heteroaryl comprising one or two 5- or6-membered rings and 1-4 heteroatoms selected from N, O and S; and R₇and R₈ are each, independently, H or hydroxyl.
 11. (canceled) 12.(canceled)
 13. (canceled)
 14. (canceled)
 15. A compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein R₁ is cyclopropylor cyclobutyl; X is H, hydroxyl, or methoxy; Y and Z are each,independently, H, hydroxyl, or NR₅R₆ wherein R₅ and R₆ are eachindependently H, alkyl or substituted acyl, or alternatively, Y and Z,together with the carbon atom to which they are attached, form C═O orC═CH₂; R₃ is H or hydroxyl; and R₂ is —C(O)NH₂, or —NH—CH₂-phenyl,wherein the phenyl can be substituted.
 16. (canceled)
 17. (canceled) 18.(canceled)
 19. (canceled)
 20. The compound of claim 15 selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim1, wherein the compound is a μ opioid receptor agonist having an Emax of5% to 45% in a GTPγS binding assay.
 22. The compound of claim 21,wherein the Emax is 15% to 35% in a GTPγS binding assay.
 23. (canceled)24. The compound of claim 1, having a maximal dopamine efflux in thenucleus accumbens of 125% to 300% over baseline in a rat.
 25. Thecompound of claim 24, having a maximal dopamine efflux in the nucleusaccumbens of 200% to 300% over baseline in a rat.
 26. The compound ofclaim 1, wherein the compound does not attenuate thermal pain in arodent hot plate model when administered at a dose of at least 1 mg/kg.27. The compound of claim 26, wherein the compound does not attenuatethermal pain in a rodent hot plate model when administered at a dose ofat least 3 mg/kg.
 28. The compound of claim 26, wherein the compounddoes not attenuate thermal pain in a rodent hot plate model whenadministered at a dose of 10 mg/kg.
 29. (canceled)
 30. A method oftreating a depressive symptom in a subject in need thereof, the methodcomprising administering to the subject an effective amount of a μopioid receptor agonist that exhibits an Emax of 5% to 45% in a GTPγSbinding assay.
 31. (canceled)
 32. (canceled)
 33. A method of treating adepressive symptom in a subject in need thereof, the method comprisingadministering to the subject an effective amount of a compound having amaximal dopamine efflux in the nucleus accumbens of 125% to 300% overbase line in a rat.
 34. (canceled)
 35. A method of treating a depressivesymptom in a subject in need thereof, the method comprisingadministering to the subject an effective amount of a compound that doesnot attenuate thermal pain in a rodent hot plate model when administeredat a dose of at least 1 mg/kg.
 36. (canceled)
 37. (canceled)
 38. Amethod of treating a depressive symptom in a subject in need thereof,comprising administering to the subject the compound of claim 1, or apharmaceutically acceptable salt thereof.
 39. (canceled)
 40. (canceled)41. The method of claim 30, wherein the depressive symptom is acutestress disorder, adjustment disorders with depressed mood, Aspergersyndrome, attention deficit, bereavement, bipolar I disorder, bipolar IIdisorder, borderline and personality disorder, cyclothymia anddysthymia, depression such as major depressive disorder (MDD) andtreatment-resistant disorder (TRD), Dysthymic disorder, hyperactivitydisorder, impulse control disorder, mixed mania, obsessive-compulsivepersonality disorder (OCD), paranoid, post-traumatic stress disorder,seasonal affective disorder, self-injury separation, sleep disorder,substance-induced mood disorder, Tourette syndrome and tic disorder,and/or Trichotillomania.
 42. (canceled)
 43. (canceled)
 44. A method oftreating a disease or condition associated with the group consisting ofpain, pruritis, diarrhea, irritable bowel syndrome, gastrointestinalmotility disorder, obesity, respiratory depression, convulsions,coughing, hyperalgesia, and drug addiction in a subject comprisingadministering to the subject a pharmaceutical composition comprising thecompound of claim 1, or a pharmaceutically acceptable salt thereof. 45.(canceled)
 46. A method of treating a disease or condition in a subjectby altering a response mediated by an opioid receptor comprisingbringing into contact with the opioid receptor an effective amount ofthe compound of claim
 1. 47. (canceled)